glycogen and Fatty-Liver

Gluconeogenesis is a crucial process to support glucose homeostasis when nutritional supply with glucose is insufficient. Because ingested carbohydrates are efficiently fermented to short-chain fatty acids in the rumen, ruminants are required to meet the largest part of their glucose demand by de novo genesis after weaning. The qualitative difference to nonruminant species is that propionate originating from ruminal metabolism is the major substrate for gluconeogenesis. Disposal of propionate into gluconeogenesis via propionyl-CoA carboxylase, methylmalonyl-CoA mutase, and the cytosolic form of phosphoenolpyruvate carboxykinase (PEPCK) has a high metabolic priority and continues even if glucose is exogenously supplied. Gluconeogenesis is regulated at the transcriptional and several posttranscriptional levels and is under hormonal control (primarily insulin, glucagon, and growth hormone). Transcriptional regulation is relevant for regulating precursor entry into gluconeogenesis (propionate, alanine and other amino acids, lactate, and glycerol). Promoters of the bovine pyruvate carboxylase (PC) and PEPCK genes are directly controlled by metabolic products. The final steps decisive for glucose release (fructose 1,6-bisphosphatase and glucose 6-phosphatase) appear to be highly dependent on posttranscriptional regulation according to actual glucose status. Glucogenic precursor entry, together with hepatic glycogen dynamics, is mostly sufficient to meet the needs for hepatic glucose output except in high-producing dairy cows during the transition from the dry period to peak lactation. Lactating cows adapt to the increased glucose requirement for lactose production by mobilization of endogenous glucogenic substrates and increased hepatic PC expression. If these adaptations fail, lipid metabolism may be altered leading to fatty liver and ketosis. Increasing feed intake and provision of glucogenic precursors from the diet are important to ameliorate these disturbances. An improved understanding of the complex mechanisms underlying gluconeogenesis may further improve our options to enhance the postpartum health status of dairy cows.

Topics: Amino Acids; Animal Feed; Animals; Cattle; Fatty Liver; Female; Gene Expression Regulation; Gluconeogenesis; Glucose; Glycogen; Hormones; Humans; Ketosis; Lactation; Lactic Acid; Methylmalonyl-CoA Decarboxylase; Methylmalonyl-CoA Mutase; Mice; Milk; Phosphoenolpyruvate Carboxykinase (GTP); Propionates; Pyruvate Carboxylase; Rats

Abnormal liver tests, right upper quadrant pain and hepatomegaly occurring in an obese or in a diabetic patient may point to the presence of fat or of glycogen accumulation in the liver parenchymal cells. Marked hepatomegaly due to cytoplasmic glycogen deposition is mainly found in poorly controlled insulin-dependent diabetic patients. If accompanied by cushingoid features, growth retardation and by delayed puberty, a diagnosis of Mauriac syndrome can be made. Hyperglycaemia, insulin administration and increased concentrations of the counterregulatory hormone cortisol may all play a role in the glycogen deposition by their concerted actions on the glycogen phosphorylase and synthase enzymes, promoting the accumulation of glycogen. Hypercortisolism may be responsible for growth retardation and delayed puberty in Mauriac patients. Regression of hepatomegaly and of the associated clinical characteristics may be obtained by a better metabolic control due to the administration of long-acting insulin and the change from single to twice daily injections. Fatty liver is rare in insulin-dependent diabetic patients and is indicative of a poor diabetic control. This process is quickly reversible by adequate insulin treatment. Steatosis is frequently found in maturity-onset diabetics and in obese patients. The pathogenetic mechanisms leading to the accumulation of triglycerides and of fatty acids in the hepatocytes can easily be understood from the normal cycling of fatty acids between the adiopose tissue and the liver. Histologic features of nonalcoholic steatohepatitis can also be found in obese and in diabetic patients. Steatohepatitis may rarely evolve into cirrhosis. In general, there is no correlation between the degree of the biochemical alterations and the severity of the histological findings.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Diabetes Complications; Diabetes Mellitus; Fatty Acids; Fatty Liver; Glycogen; Humans; Liver; Obesity; Triglycerides

Topics: Alcoholic Intoxication; Alcoholism; Animals; Chemical and Drug Induced Liver Injury; Ethanol; Fats; Fatty Liver; Glucose; Glycogen; Hepatomegaly; Humans; Lipid Metabolism; Liver; Liver Cirrhosis; Microsomes, Liver; Social Problems

Topics: Age Factors; Albumins; Animals; Antineoplastic Agents; Cell Division; Dogs; Fatty Liver; Glycogen; Hepatectomy; Hormones; Lipid Metabolism; Liver; Liver Function Tests; Liver Regeneration; Mice; Microscopy, Electron; Mitosis; Organ Size; Polyploidy; Rats; Water

Topics: Diabetes Mellitus; Fatty Liver; Glycogen; Hemochromatosis; Hepatitis; Hepatitis A; Humans; Insulin; Liver; Liver Cirrhosis

Topics: Alanine Transaminase; Aspartate Aminotransferases; Clinical Enzyme Tests; Diabetes Mellitus; Fatty Liver; Glycogen; Glycogen Storage Disease; Hepatitis; Hepatitis A; Humans; Jaundice; Liver Cirrhosis; Liver Diseases; Liver Glycogen; Splenomegaly

Topics: Aged; Blood Glucose; Cholesterol; Clinical Trials as Topic; Diabetes Complications; Fatty Acids, Nonesterified; Fatty Liver; Female; Glycogen; Humans; Lipids; Liver; Middle Aged; Phospholipids; Placebos; Tolbutamide; Triglycerides

Topics: Animals; Cattle; Cattle Diseases; Cholesterol; Choline; Diet; Dietary Supplements; Fatty Acids; Fatty Liver; Female; Glucose; Glycogen; Haptoglobins; Inflammation; Lactation; Liver; Methionine; Milk; Pregnancy; RNA, Messenger; Rumen; Triglycerides

Objectives were to determine the effects of supplementing increasing amounts of choline ion on hepatic composition and mRNA abundance in pregnant dry cows subjected to a fatty liver induction protocol. Holstein cows (35 primiparous and 41 multiparous) at mean (± standard deviation) of 211 ± 9.9 days of gestation were blocked by body condition (3.59 ± 0.33) and assigned to receive 0, 6.45, 12.90, 19.35, and 25.80 g/day of choline ion as rumen-protected choline (RPC) as a top-dress for 14 days. Cows were fed for ad libitum intake on days 1 to 5 and restricted to 30% of the required net energy for lactation from days 6 to 14 of the experiment. Hepatic tissue was sampled on days 5 and 14 and analyzed for concentrations of triacylglycerol and glycogen, and mRNA abundance was investigated. Orthogonal contrasts evaluated the effects of supplementing RPC (0 g/day vs. rest), and the linear, quadratic, and cubic effects of increasing intake of choline ion from 6.45 to 25.80 g/day. Results are depicted in sequence of treatments from 0 to 25.8. During feed restriction, RPC reduced the concentration of hepatic triacylglycerol by 28.5% and increased that of glycogen by 26.1%, and the effect of increasing RPC intake on triacylglycerol was linear (6.67 vs. 5.45 vs. 4.68 vs. 5.13 vs. 3.81 ± 0.92% wet-basis). Feeding RPC during feed restriction increased abundance of transcripts involved in choline metabolism (CHKA, PLD1), synthesis of apolipoprotein-B100 (APOB100), and antioxidant activity (GPX3), and decreased the abundance of transcripts involved in hepatic lipogenesis (DGAT2, SREBF1) and acute phase response (SAA3). Most effects were linear with amount of choline fed. Changes in hepatic mRNA abundance followed a pattern of reduced lipogenesis and enhanced lipids export, which help explain the reduced hepatic triacylglycerol content in cows fed RPC. Choline exerts lipotropic effects in dairy cows by altering transcript pathways linked to hepatic lipids metabolism.

Topics: Animals; Cattle; Choline; Diet; Dietary Supplements; Fatty Liver; Female; Glycogen; Lactation; Liver; Milk; Pregnancy; RNA, Messenger; Rumen; Triglycerides

Fatty liver is an abnormal metabolic condition of excess intrahepatic fat. This condition, referred to as hepatic steatosis, is tightly associated with chronic liver disease and systemic metabolic morbidity. The most prevalent form in humans, i.e. non-alcoholic fatty liver, generally develops due to overnutrition and sedentary lifestyle, and has as yet no approved drug therapy. Previously, we have developed a relevant large-animal model in which overnourished sheep raised on a high-calorie carbohydrate-rich diet develop hyperglycemia, hyperinsulinemia, insulin resistance, and hepatic steatosis. Here, we tested the hypothesis that treatment with thiamine (vitamin B1) can counter the development of hepatic steatosis driven by overnutrition. Remarkably, the thiamine-treated animals presented with completely normal levels of intrahepatic fat, despite consuming the same amount of liver-fattening diet. Thiamine treatment also decreased hyperglycemia and increased the glycogen content of the liver, but it did not improve insulin sensitivity, suggesting that steatosis can be addressed independently of targeting insulin resistance. Thiamine increased the catalytic capacity for hepatic oxidation of carbohydrates and fatty acids. However, at gene-expression levels, more-pronounced effects were observed on lipid-droplet formation and lipidation of very-low-density lipoprotein, suggesting that thiamine affects lipid metabolism not only through its known classic coenzyme roles. This discovery of the potent anti-steatotic effect of thiamine may prove clinically useful in managing fatty liver-related disorders.This article has an associated First Person interview with the joint first authors of the paper.

Topics: Adiposity; Animals; Blood Glucose; Cytokines; Diet, High-Fat; Dose-Response Relationship, Drug; Fatty Acids; Fatty Liver; Gene Expression Regulation; Glycogen; Inflammation Mediators; Ketoglutarate Dehydrogenase Complex; Lipid Metabolism; Liver; Male; Mitochondria; Overnutrition; RNA, Messenger; Sheep; Thiamine; Thiamine Pyrophosphate; Weight Gain

Fatal starvation is rarely seen in developed countries; when it occurs, it may be associated with medicolegal problems. Forensic pathologists are required to determine leading causes of death and provide opinions on the influence of starvation, especially in cases of suspected child abuse. Recently, starvation-induced steatosis was suggested to be regulated by lipophagy. Here, we report an extremely rare case of death by malnutrition of a 10-year-old boy, who was fed only infant formula throughout his life. The deceased presented with severe hepatic steatosis, probably related to prolonged malnutrition. Fatty liver changes, with deposition of small lipid droplets deposited in the peripheral lobules. High levels of P62 protein (overexpression of which indicates an autophagy impairment) were seen around the central vein region, whereas light-chain-3 (LC3) protein (an indicator of lipophagy activation) was unremarkable. Thus, in our case, impaired lipophagy influenced starvation-induced steatosis. To our knowledge, this article is the first to evaluate the application of lipophagy in forensic investigations as an objective diagnostic criterion.

Topics: Autophagy; Child; Child Nutrition Disorders; Dehydration; Fatal Outcome; Fatty Liver; Glycogen; Humans; Infant; Infant Formula; Liver; Male; RNA-Binding Proteins; Starvation

Impairment of glucose (Glu) uptake and storage by skeletal muscle is a prime risk factor for the development of metabolic diseases. Heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) is a highly abundant RNA-binding protein that has been implicated in diverse cellular functions. The aim of this study was to investigate the function of hnRNP A1 on muscle tissue insulin sensitivity and systemic Glu homeostasis. Our results showed that conditional deletion of hnRNP A1 in the muscle gave rise to a severe insulin resistance phenotype in mice fed a high-fat diet (HFD). Conditional knockout mice fed a HFD showed exacerbated obesity, insulin resistance, and hepatic steatosis. In vitro interference of hnRNP A1 in C2C12 myotubes impaired insulin signal transduction and inhibited Glu uptake, whereas hnRNP A1 overexpression in C2C12 myotubes protected against insulin resistance induced by supraphysiological concentrations of insulin. The expression and stability of glycogen synthase (gys1) mRNA were also decreased in the absence of hnRNP A1. Mechanistically, hnRNP A1 interacted with gys1 and stabilized its mRNA, thereby promoting glycogen synthesis and maintaining the insulin sensitivity in muscle tissue. Taken together, our findings are the first to show that reduced expression of hnRNP A1 in skeletal muscle affects the metabolic properties and systemic insulin sensitivity by inhibiting glycogen synthesis.

Topics: Animals; Cell Line; Diabetes Mellitus, Experimental; Diet, High-Fat; Fatty Liver; Glycogen; Glycogen Synthase; Heterogeneous Nuclear Ribonucleoprotein A1; Insulin Resistance; Male; Mice, Knockout; Models, Biological; Muscle Fibers, Skeletal; Muscle, Skeletal; RNA Stability; Severity of Illness Index

Growth hormone (GH) has an important function as an insulin antagonist with elevated insulin sensitivity evident in humans and mice lacking a functional GH receptor (GHR). We sought the molecular basis for this sensitivity by utilizing a panel of mice possessing specific deletions of GHR signaling pathways. Metabolic clamps and glucose homeostasis tests were undertaken in these obese adult C57BL/6 male mice, which indicated impaired hepatic gluconeogenesis. Insulin sensitivity and glucose disappearance rate were enhanced in muscle and adipose of mice lacking the ability to activate the signal transducer and activator of transcription (STAT)5

Topics: Animals; Carrier Proteins; Fatty Liver; Glucose; Glycogen; Insulin Receptor Substrate Proteins; Insulin Resistance; Intracellular Signaling Peptides and Proteins; Liver; Male; Mice; Mice, Knockout; Obesity; Phosphoenolpyruvate Carboxykinase (GTP); Receptor, Insulin; Signal Transduction; STAT5 Transcription Factor

Skeletal muscle plays a central role in the control of metabolism and exercise tolerance. Analysis of muscle enhancers activated after exercise in mice revealed the orphan nuclear receptor NURR1/NR4A2 as a prominent component of exercise-responsive enhancers. We show that exercise enhances the expression of NURR1, and transgenic overexpression of NURR1 in skeletal muscle enhances physical performance in mice. NURR1 expression in skeletal muscle is also sufficient to prevent hyperglycemia and hepatic steatosis, by enhancing muscle glucose uptake and storage as glycogen. Furthermore, treatment of obese mice with putative NURR1 agonists increases energy expenditure, improves glucose tolerance, and confers a lean phenotype, mimicking the effects of exercise. These findings identify a key role for NURR1 in governance of skeletal muscle glucose metabolism, and reveal a transcriptional link between exercise and metabolism. Our findings also identify NURR1 agonists as possible exercise mimetics with the potential to ameliorate obesity and other metabolic abnormalities.

Topics: Animals; Carbohydrate Metabolism; Energy Metabolism; Fatty Liver; Glucose; Glycogen; Homeostasis; Humans; Hyperglycemia; Liver; Male; Mice; Mice, Inbred C57BL; Muscle, Skeletal; Nuclear Receptor Subfamily 4, Group A, Member 2; Obesity; Physical Conditioning, Animal; Transcription, Genetic; Up-Regulation

Topics: Animals; Autophagy; Disease Models, Animal; Fatty Acids; Fatty Liver; Glucose-6-Phosphatase; Glycogen; Glycogen Storage Disease Type I; Liver; Mice; Mice, Knockout; Mitochondria, Liver; Organelle Biogenesis; Organophosphonates; Oxidation-Reduction; Thyroid Hormone Receptors beta; Triglycerides

Transient hepatic steatosis upon liver resection supposes functional relationships between lipid metabolism and liver regeneration. Repin1 has been suggested as candidate gene for obesity and dyslipidemia by regulating key genes of lipid metabolism and lipid storage. Herein, we characterized the regenerative potential of mice with a hepatic deletion of Repin1 (LRep1-/-) after partial hepatectomy (PH) in order to determine the functional significance of Repin1 in liver regeneration. Lipid dynamics and the regenerative response were analyzed at various time points after PH. Hepatic Repin1 deficiency causes a significantly decreased transient hepatic lipid accumulation. Defects in lipid uptake, as analyzed by decreased expression of the fatty acid transporter Cd36 and Fatp5, may contribute to attenuated and shifted lipid accumulation, accompanied by altered extent and chronological sequence of liver cell proliferation in LRep1-/- mice. In vitro steatosis experiments with primary hepatocytes also revealed attenuated lipid accumulation and occurrence of smaller lipid droplets in Repin1-deficient cells, while no direct effect on proliferation in HepG2 cells was observed. Based on these results, we propose that hepatocellular Repin1 might be of functional significance for early accumulation of lipids in hepatocytes after PH, facilitating efficient progression of liver regeneration.

Topics: Animals; Cell Proliferation; DNA-Binding Proteins; Fatty Acids; Fatty Liver; Glycogen; Hep G2 Cells; Hepatocytes; Humans; Lipid Metabolism; Liver; Liver Function Tests; Liver Regeneration; Male; Mice, Inbred C57BL; Organ Specificity; RNA-Binding Proteins; RNA, Messenger

Disruption of the

Topics: Acetyl-CoA Carboxylase; Active Transport, Cell Nucleus; Animals; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; Cell Nucleus; Fatty Liver; Forkhead Box Protein O1; Glycogen; Glycogen Synthase Kinase 3; Hepatocytes; Insulin Receptor Substrate Proteins; Insulin Resistance; Mice; Mice, Knockout; Nuclear Proteins; Phosphorylation; Proto-Oncogene Proteins c-akt; Signal Transduction; Sterol Regulatory Element Binding Protein 1; Transcription Factors

The ability to adapt cellular metabolism to nutrient availability is critical for survival. The liver plays a central role in the adaptation to starvation by switching from glucose-consuming processes and lipid synthesis to providing energy substrates like glucose to the organism. Here we report a previously unrecognized role of the tumor suppressor p53 in the physiologic adaptation to food withdrawal. We found that starvation robustly increases p53 protein in mouse liver. This induction was posttranscriptional and mediated by a hepatocyte-autonomous and AMP-activated protein kinase-dependent mechanism. p53 stabilization was required for the adaptive expression of genes involved in amino acid catabolism. Indeed, acute deletion of p53 in livers of adult mice impaired hepatic glycogen storage and induced steatosis. Upon food withdrawal, p53-deleted mice became hypoglycemic and showed defects in the starvation-associated utilization of hepatic amino acids. In summary, we provide novel evidence for a p53-dependent integration of acute changes of cellular energy status and the metabolic adaptation to starvation. Because of its tumor suppressor function, p53 stabilization by starvation could have implications for both metabolic and oncological diseases of the liver.-Prokesch, A., Graef, F. A., Madl, T., Kahlhofer, J., Heidenreich, S., Schumann, A., Moyschewitz, E., Pristoynik, P., Blaschitz, A., Knauer, M., Muenzner, M., Bogner-Strauss, J. G., Dohr, G., Schulz, T. J., Schupp, M. Liver p53 is stabilized upon starvation and required for amino acid catabolism and gluconeogenesis.

Topics: Adenylate Kinase; Animals; Cells, Cultured; Fatty Liver; Food Deprivation; Gene Deletion; Gene Expression Regulation; Gene Silencing; Glycogen; Hep G2 Cells; Hepatocytes; Humans; Liver; Male; Mice; Mice, Inbred C57BL; Signal Transduction; Transcriptome; Tumor Suppressor Protein p53

Glycogen and triglyceride are two major forms of energy storage in the body and provide the fuel during different phases of food deprivation. However, how glycogen metabolism is linked to fat deposition in adipose tissue has not been clearly characterized. We generated a mouse model with whole-body deletion of PPP1R3G, a glycogen-targeting subunit of protein phosphatase-1 required for glycogen synthesis. Upon feeding with high-fat diet, the body weight and fat composition are significantly reduced in the PPP1R3G

Topics: 3T3-L1 Cells; Adipocytes; Animals; Basal Metabolism; Blood Glucose; Diet, High-Fat; Fatty Liver; Gene Deletion; Glycogen; Insulin Resistance; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Obesity; Postprandial Period; Protein Phosphatase 1; Triglycerides

Nonalcoholic fatty liver disease (NAFLD) is a serious health problem in developed countries. We documented the effects of feeding with a NAFLD-inducing, methionine- and choline-deficient (MCD) diet, for 1-4 weeks on rat liver oxidative stress, with respect to a control diet. Glycogen, neutral lipids, ROS, peroxidated proteins, and SOD2 were investigated using histochemical procedures; ATP, GSH, and TBARS concentrations were investigated by biochemical dosages, and SOD2 expression was investigated by Western Blotting. In the 4-week-diet period, glycogen stores decreased whereas lipid droplets, ROS, and peroxidated proteins expression (especially around lipid droplets of hepatocytes) increased. SOD2 immunostaining decreased in poorly steatotic hepatocytes but increased in the thin cytoplasm of macrosteatotic cells; a trend towards a quantitative decrease of SOD expression in homogenates occurred after 3 weeks. ATP and GSH values were significantly lower for rats fed with the MCD diet with respect to the controls. An increase of TBARS in the last period of the diet is in keeping with the high ROS production and low antioxidant defense; these TBARS may promote protein peroxidation around lipid droplets. Since these proteins play key roles in lipid mobilization, storage, and metabolism, this last information appears significant, as it points towards a previously misconsidered target of NAFLD-associated oxidative stress that might be responsible for lipid dysfunction.

Topics: Adenosine Triphosphate; Animals; Blotting, Western; Choline; Diet; Fatty Liver; Glutathione; Glycogen; Hydrazines; Immunohistochemistry; Liver; Male; Methionine; Oxidative Stress; Protein Carbonylation; Rats, Wistar; Reactive Oxygen Species; Superoxide Dismutase; Thiobarbituric Acid Reactive Substances

Ectopic lipid accumulation in the liver is an almost universal feature of human and rodent models of generalized lipodystrophy and is also a common feature of type 2 diabetes, obesity, and metabolic syndrome. Here we explore the progression of fatty liver disease using a mouse model of lipodystrophy created by a fat-specific knockout of the insulin receptor (F-IRKO) or both IR and insulin-like growth factor 1 receptor (F-IR/IGFRKO). These mice develop severe lipodystrophy, diabetes, hyperlipidemia, and fatty liver disease within the first weeks of life. By 12 weeks of age, liver demonstrated increased reactive oxygen species, lipid peroxidation, histological evidence of balloon degeneration, and elevated serum alanine aminotransferase and aspartate aminotransferase levels. In these lipodystrophic mice, stored liver lipids can be used for energy production, as indicated by a marked decrease in liver weight with fasting and increased liver fibroblast growth factor 21 expression and intact ketogenesis. By 52 weeks of age, liver accounted for 25% of body weight and showed continued balloon degeneration in addition to inflammation, fibrosis, and highly dysplastic liver nodules. Progression of liver disease was associated with improvement in blood glucose levels, with evidence of altered expression of gluconeogenic and glycolytic enzymes. However, these mice were able to mobilize stored glycogen in response to glucagon. Feeding F-IRKO and F-IR/IGFRKO mice a high-fat diet for 12 weeks accelerated the liver injury and normalization of blood glucose levels. Thus, severe fatty liver disease develops early in lipodystrophic mice and progresses to advanced nonalcoholic steatohepatitis with highly dysplastic liver nodules. The liver injury is propagated by lipotoxicity and is associated with improved blood glucose levels.

Topics: Adipose Tissue; Alanine Transaminase; Animals; Blood Glucose; Diet, High-Fat; Disease Models, Animal; Fatty Liver; Fibroblast Growth Factors; Glucose Tolerance Test; Glycogen; Immunoblotting; Immunohistochemistry; Insulin-Like Growth Factor I; Lipodystrophy; Liver; Mice; Mice, Knockout; Non-alcoholic Fatty Liver Disease; Receptor, Insulin

Resistance to the action of insulin affects fatty acid delivery to the liver, fatty acid synthesis and oxidation within the liver, and triglyceride export from the liver. To understand the metabolic consequences of hepatic fatty acid synthesis, partitioning, oxidation, and net liver fat content in the fasted and postprandial states, we used stable-isotope tracer methodologies to study healthy men and women with varying degrees of insulin resistance before and after consumption of a mixed meal. Subjects were classified as being normoinsulinemic (NI) (fasting plasma insulin <11.2 mU/L, n = 18) or hyperinsulinemic (HI) (fasting plasma insulin >11.2 mU/L, n = 19). Liver fat content was similar between HI and NI individuals, despite HI subjects having marginally more visceral fat. However, de novo lipogenesis was higher and fatty acid oxidation was lower in HI individuals compared with NI subjects. These data suggest that metabolic pathways promoting fat accumulation are enhanced in HI but, paradoxically, without any significant effect on liver fat content when observed in healthy people. This is likely to be explained by increased triglyceride secretion as observed by hypertriglyceridemia.

Topics: Adipose Tissue; Adult; Blood Glucose; Body Composition; Fasting; Fatty Acids; Fatty Liver; Female; Glycogen; Humans; Insulin; Insulin Resistance; Lipid Metabolism; Liver; Male; Middle Aged

The common complications in obesity and type 2 diabetes include hepatic steatosis and disruption of glucose-glycogen homeostasis, leading to hyperglycemia. Fatty acid translocase (FAT/CD36), whose expression is inducible in obesity, is known for its function in fatty acid uptake. Previous work by us and others suggested that CD36 plays an important role in hepatic lipid homeostasis, but the results have been conflicting and the mechanisms were not well understood. In this study, by using CD36-overexpressing transgenic (CD36Tg) mice, we uncovered a surprising function of CD36 in regulating glycogen homeostasis. Overexpression of CD36 promoted glycogen synthesis, and as a result, CD36Tg mice were protected from fasting hypoglycemia. When challenged with a high-fat diet (HFD), CD36Tg mice showed unexpected attenuation of hepatic steatosis, increased very low-density lipoprotein (VLDL) secretion, and improved glucose tolerance and insulin sensitivity. The HFD-fed CD36Tg mice also showed decreased levels of proinflammatory hepatic prostaglandins and 20-hydroxyeicosatetraenoic acid (20-HETE), a potent vasoconstrictive and proinflammatory arachidonic acid metabolite. We propose that CD36 functions as a protective metabolic sensor in the liver under lipid overload and metabolic stress. CD36 may be explored as a valuable therapeutic target for the management of metabolic syndrome.

Topics: Animals; Arachidonic Acid; CD36 Antigens; Diet, High-Fat; Fasting; Fatty Liver; Glycogen; Homeostasis; Hydroxyeicosatetraenoic Acids; Hypoglycemia; Insulin Resistance; Liver; Mice, Transgenic; Oxygen Consumption; Prostaglandins

In humans, low levels of growth hormone (GH) and its mediator, IGF-1, associate with hepatic lipid accumulation. In mice, congenital liver-specific ablation of the GH receptor (GHR) results in reductions in circulating IGF-1 and hepatic steatosis, associated with systemic insulin resistance. Due to the intricate relationship between GH and IGF-1, the relative contribution of each hormone to the development of hepatic steatosis is unclear. Our goal was to dissect the mechanisms by which hepatic GH resistance leads to steatosis and overall insulin resistance, independent of IGF-1. We have generated a combined mouse model with liver-specific ablation of GHR in which we restored liver IGF-1 expression via the hepatic IGF-1 transgene. We found that liver GHR ablation leads to increases in lipid uptake, de novo lipogenesis, hyperinsulinemia, and hyperglycemia accompanied with severe insulin resistance and increased body adiposity and serum lipids. Restoration of IGF-1 improved overall insulin sensitivity and lipid profile in serum and reduced body adiposity, but was insufficient to protect against steatosis-induced hepatic inflammation or oxidative stress. We conclude that the impaired metabolism in states of GH resistance results from direct actions of GH on lipid uptake and de novo lipogenesis, whereas its actions on extrahepatic tissues are mediated by IGF-1.

Topics: Animals; Blotting, Western; Fatty Acids; Fatty Acids, Nonesterified; Fatty Liver; Glycogen; Growth Hormone; Hyperinsulinism; Insulin Resistance; Insulin-Like Growth Factor I; Lipid Metabolism; Lipid Peroxidation; Liver; Male; Mice; Mice, Knockout; Oxidative Stress; Receptors, Somatotropin

Topics: Biopsy; Fatty Liver; Glycogen; Humans; Liver; Non-alcoholic Fatty Liver Disease

The present study analyzes the effect of the replacement of dietary casein by soy protein on the mechanisms underlying dyslipidemia, liver steatosis and altered glucose and lipid metabolism in the skeletal muscle which developed in rats fed long-term a sucrose-rich diet (SRD).. Wistar rats were fed a SRD for 4 months. From months 4 to 8, half the animals continued with the SRD, and the other half were fed a SRD in which the source of protein casein was replaced by soy. The control group received a diet with cornstarch as source of carbohydrate.. Compared to SRD-fed animals, the rats fed soy showed: A--in the liver: reduction of triglyceride and cholesterol storage and decreased steatosis; normalization of mature forms of the protein mass levels of SREBP-1 and the activities of lipogenic enzymes, while the protein mass level of PPAR-α and fatty acid oxidase activity increased. B-in the gastrocnemius muscle: normalization of the enhanced lipid storage and the altered glucose oxidation, improving glucose phosphorylation; decreasing protein mass level of nPKCθ in the membrane fraction; reversion of the impaired insulin-stimulated glucose transporter Glut-4, and glucose-6-phosphate and glycogen concentrations. Besides, dyslipidemia and glucose homeostasis returned to control values.. This study provides new information concerning some key mechanisms related to the effect of dietary soy on hepatic lipid metabolism and insulin action in the skeletal muscle in the presence of pre-existing dyslipidemia and insulin resistance induced by a SRD.

Topics: Animals; Blood Glucose; Cholesterol; Dietary Sucrose; Dyslipidemias; Fatty Acids, Nonesterified; Fatty Liver; Glucose Transporter Type 4; Glucose-6-Phosphate; Glycogen; Insulin; Insulin Resistance; Lipid Metabolism; Liver; Male; Muscle, Skeletal; PPAR alpha; Rats; Rats, Wistar; Soybean Proteins; Sterol Regulatory Element Binding Protein 1; Triglycerides; Weight Gain

The phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) catalytic subunit p110α is the most frequently mutated kinase in human cancer, and the hot spot mutations E542K, E545K, and H1047R are the most common mutations in p110α. Very little is known about the metabolic consequences of the hot spot mutations of p110α in vivo. In this study, we used adenoviral gene transfer in mice to investigate the effects of the E545K and H1047R mutations on hepatic and whole-body glucose metabolism. We show that hepatic expression of these hot spot mutations results in rapid hepatic steatosis, paradoxically accompanied by increased glucose tolerance, and marked glycogen accumulation. In contrast, wild-type p110α expression does not lead to hepatic accumulation of lipids or glycogen despite similar degrees of upregulated glycolysis and expression of lipogenic genes. The reprogrammed metabolism of the E545K and H1047R p110α mutants was surprisingly not dependent on altered p110α lipid kinase activity.

Topics: Animals; Class I Phosphatidylinositol 3-Kinases; Energy Metabolism; Enzyme Activation; Fatty Acids; Fatty Liver; Glucose Intolerance; Glycogen; Glycolysis; Lipid Metabolism; Liver; Male; Mice, Knockout; Mutation, Missense; Oxidation-Reduction; Phosphorylation; Protein Processing, Post-Translational; Proto-Oncogene Proteins c-akt; Signal Transduction

Obese leptin deficient (ob/ob) mice are a model of adiposity that displays increased levels of fat, glucose, and liver lipids. Our hypothesis is that HO-1 overexpression ameliorates fatty liver development.. Obese mice were administered cobalt protoporphyrin (CoPP) and stannic mesoporphyrin (SnMP) for 6 weeks. Heme, HO-1, HO activity, PGC1α, FGF21, glycogen content, and lipogenesis were assessed.. CoPP administration increased hepatic HO-1 protein levels and HO activity, decreased hepatic heme, body weight gain, glucose levels, and resulted in decreased steatosis. Increased levels of HO-1 produced a decrease in lipid droplet size, Fatty acid synthase (FAS) levels involving recruitment of FGF21, PPARα, and Glut 1. These beneficial effects were reversed by inhibition of HO activity.. Increased levels of HO-1 and HO activity reduced the levels of obesity by reducing hepatic heme and lipid accumulation. These changes were manifested by decreases in cellular heme, increases in FGF21, glycogen content, and fatty liver. The beneficial effect of HO-1 induction results from an increase in PPARα and FGF21 levels and a decrease in PGC1α, levels they were reversed by SnMP. Low levels of HO-1 and HO activity are responsible for fatty liver.

Topics: Adiposity; Animals; Fatty Liver; Fibroblast Growth Factors; Glucose Transporter Type 1; Glycogen; Heme; Heme Oxygenase-1; Leptin; Liver; Male; Membrane Proteins; Mesoporphyrins; Mice; Mice, Obese; Obesity; PPAR alpha; Protoporphyrins; Tin Compounds; Transcription Factors; Weight Gain

Leptin is essential for energy homeostasis and regulation of food intake. Patients with congenital generalized lipodystrophy (CGL) due to mutations in 1-acylglycerol-3-phosphate-O-acyltransferase 2 (AGPAT2) and the CGL murine model (Agpat2(-/-) mice) both have severe insulin resistance, diabetes mellitus, hepatic steatosis, and low plasma leptin levels. In this study, we show that continuous leptin treatment of Agpat2(-/-) mice for 28 days reduced plasma insulin and glucose levels and normalized hepatic steatosis and hypertriglyceridemia. Leptin also partially, but significantly, reversed the low plasma thyroxine and high corticosterone levels found in Agpat2(-/-) mice. Levels of carbohydrate response element binding protein (ChREBP) were reduced, whereas lipogenic gene expression were increased in the livers of Agpat2(-/-) mice, suggesting that deregulated ChREBP contributed to the development of fatty livers in these mice and that this transcription factor is a target of leptin's beneficial metabolic action. Leptin administration did not change hepatic fatty acid oxidation enzymes mRNA levels in Agpat2(-/-) mice. The selective deletion of leptin receptors only in hepatocytes did not prevent the positive metabolic actions of leptin in Agpat2(-/-) mice, supporting the notion that the majority of metabolic actions of leptin are dependent on its action in nonhepatocyte cells and/or the central nervous system.

Topics: 1-Acylglycerol-3-Phosphate O-Acyltransferase; Animals; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; Corticosterone; Fatty Acids; Fatty Liver; Gene Deletion; Gene Expression Regulation; Glucose; Glycogen; Hepatocytes; Insulin Resistance; Leptin; Lipodystrophy; Lipogenesis; Liver; Male; Mice; Nuclear Proteins; Oxidation-Reduction; Phosphorylation; Proto-Oncogene Proteins c-akt; Receptors, Leptin; Thyroxine; Transcription Factors; Transcription, Genetic; Triglycerides

Mammalian tribbles homolog 1 (TRIB1) regulates hepatic lipogenesis and is genetically associated with plasma triglyceride (TG) levels and cholesterol, but the molecular mechanisms remain obscure. We explored these mechanisms in mouse livers transfected with a TRIB1 overexpression, a shRNA template or a control (LacZ) adenovirus vector. The overexpression of TRIB1 reduced, whereas induction of the shRNA template increased, plasma glucose, TG, and cholesterol and simultaneously hepatic TG and glycogen levels. The involvement of TRIB1 in hepatic lipid accumulation was supported by the findings of a human SNP association study. A TRIB1 SNP, rs6982502, was identified in an enhancer sequence, modulated enhancer activity in reporter gene assays, and was significantly (P=9.39 × 10(-7)) associated with ultrasonographically diagnosed non-alcoholic fatty liver disease in a population of 5570 individuals. Transcriptome analyses of mouse livers revealed significant modulation of the gene sets involved in glycogenolysis and lipogenesis. Enforced TRIB1 expression abolished CCAAT/enhancer binding protein A (CEBPA), CEBPB, and MLXIPL proteins, whereas knockdown increased the protein level. Levels of TRIB1 expression simultaneously affected MKK4 (MAP2K4), MEK1 (MAP2K1), and ERK1/2 (MAPK1/3) protein levels and the phosphorylation of JNK, but not of ERK1/2. Pull-down and mammalian two-hybrid analyses revealed novel molecular interaction between TRIB1 and a hepatic lipogenic master regulator, MLXIPL. Co-expression of TRIB1 and CEBPA or MLXIPL reduced their protein levels and proteasome inhibitors attenuated the reduction. These data suggested that the modulation of TRIB1 expression affects hepatic lipogenesis and glycogenesis through multiple molecular interactions.

Topics: Animals; Blood Glucose; Blotting, Western; DNA-Binding Proteins; Down-Regulation; Energy Metabolism; Fatty Liver; Female; Gene Knockdown Techniques; Genes, Reporter; Glycogen; Humans; Intracellular Signaling Peptides and Proteins; Lipogenesis; Liver; Male; Mice; Non-alcoholic Fatty Liver Disease; Organ Size; Polymorphism, Single Nucleotide; Protein Binding; Protein Serine-Threonine Kinases; Regulatory Sequences, Nucleic Acid; RNA, Messenger; Signal Transduction; Transcriptome; Triglycerides; Ultrasonography

Mauriac syndrome is characterised by growth failure, cushingoid appearance and hepatomegaly which occurs in patients with insulin dependent diabetes and was first described shortly after the introduction of insulin as a treatment for the condition.. To describe the clinical features, histological findings and outcome of young people with glycogenic hepatopathy, the hepatic manifestation of Mauriac syndrome (MS).. Retrospective cohort study.. Young people with glycogenic hepatopathy.. Tertiary paediatric hepatology unit.. Thirty-one young people (16 M), median age of 15.1 years (IQR 14-16.2) presented within the study period. Median age of diagnosis of diabetes was 10 years (IQR 8-11). Median insulin requirement was 1.33 units/kg/day; median HbA1c was 96.7 mmol/mol (IQR 84.7-112.0). Growth was impaired: median height z-score was -1.01 (-1.73 to 0.4) and median body mass index (BMI) z-score was 0.28 (-0.12 to 0.67). Hepatomegaly was universal with splenomegaly in 16%. Transaminases were abnormal with a median aspartate aminotransferase (AST) of 76 IU/L and gamma glutamyltransferase of 71 IU/L. Liver biopsy was undertaken in 19 (61%). All showed enlarged hepatocytes with clear cytoplasm with glycogenated nuclei in 17. Steatosis was present in the majority. Inflammation was present in 8 (42%). Fibrosis was seen in 14 (73%) and was generally mild though 2 had bridging fibrosis. Megamitochondria were described in 7. Presence of megamitochondria correlated with AST elevation (p=0.026) and fibrosis on biopsy (p=0.007). At follow-up 17 children had normal or improved transaminases, in 13 there was no change. Transaminases followed the trend of the child's HbA1c.. Despite modern insulin regimens and monitoring in children with type 1 diabetes, MS still exists. Significant steatosis, inflammation and fibrosis were all seen in liver biopsies.

Topics: Adolescent; Biopsy; Diabetes Mellitus, Type 1; Fatty Liver; Female; Glycogen; Growth Disorders; Hepatitis; Hepatomegaly; Humans; Liver; Liver Cirrhosis; Male; Retrospective Studies; Syndrome

Changes in the maternal nutritional environment during fetal development can influence offspring's metabolic risk in later life. Animal models have demonstrated that offspring of diet-induced obese dams develop metabolic complications, including nonalcoholic fatty liver disease. In this study we investigated the mechanisms in young offspring that lead to the development of nonalcoholic fatty liver disease (NAFLD). Female offspring of C57BL/6J dams fed either a control or obesogenic diet were studied at 8 wk of age. We investigated the roles of oxidative stress and lipid metabolism in contributing to fatty liver in offspring. There were no differences in body weight or adiposity at 8 wk of age; however, offspring of obese dams were hyperinsulinemic. Oxidative damage markers were significantly increased in their livers, with reduced levels of the antioxidant enzyme glutathione peroxidase-1. Mitochondrial complex I and II activities were elevated, while levels of mitochondrial cytochrome c were significantly reduced and glutamate dehydrogenase was significantly increased, suggesting mitochondrial dysfunction. Offspring of obese dams also had significantly greater hepatic lipid content, associated with increased levels of PPARγ and reduced triglyceride lipase. Liver glycogen and protein content were concomitantly reduced in offspring of obese dams. In conclusion, offspring of diet-induced obese dams have disrupted liver metabolism and develop NAFLD prior to any differences in body weight or body composition. Oxidative stress may play a mechanistic role in the progression of fatty liver in these offspring.

Topics: Adiposity; Age Factors; Animal Nutritional Physiological Phenomena; Animals; Body Weight; Cytochromes c; Electron Transport Complex I; Electron Transport Complex II; Fatty Liver; Female; Glutamate Dehydrogenase; Glutathione Peroxidase; Glutathione Peroxidase GPX1; Glycogen; Homeostasis; Insulin; Lipase; Lipid Metabolism; Liver; Mice; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease; Obesity; Oxidative Stress; Phenotype; PPAR gamma; Pregnancy; Prenatal Exposure Delayed Effects; Prenatal Nutritional Physiological Phenomena; Risk Factors; Signal Transduction

Aflatoxin B1 (AFB1) and the hepatitis B virus X antigen (HBx) are linked to the formation of liver diseases and hepatocellular carcinoma (HCC). The aim of this study was to investigate the synergistic effects between HBx and AFB1 in causing liver disorders using a transgenic zebrafish animal model. Histopathology, Periodic acid-Schiff (PAS) staining, Sirius red staining, TdT-mediated dUTP Nick End Labeling (TUNEL) assay, immunohistochemistry, and quantitative reverse transcriptase-polymerase chain reaction (Q-RT-PCR) were used to examine the livers of the HBx transgenic fish injected with AFB1. We found that HBx and AFB1 synergistically promoted steatosis as indicated by histopathological examinations and the increased expression of lipogenic factors, enzymes, and genes related to lipid metabolism. Moreover, treatment of AFB1 in HBx transgenic fish accelerated the development of liver hyperplasia and enhanced the expression of cell cycle related genes. PCNA was co-localized with active caspase 3 protein expression in HBx zebrafish liver samples and human HBV positive HCC samples by double fluorescence immunostaining. Finally, we found that in human patients with liver disease, significant glycogen accumulated in the inflammation, cirrhosis stage, and all cases of hepatocellular and cholangiocellular carcinoma showed a moderate cytoplasmic accumulation of glycogen. Our data demonstrated a synergistic effect of AFB1 and HBx on the regulation of lipid metabolism related genes and cell cycle/division-related genes which might contribute to enhanced steatosis and hyperplasia at 5.75months.

Topics: Aflatoxin B1; Animals; Animals, Genetically Modified; Carcinoma, Hepatocellular; Caspase 3; Cell Cycle Proteins; Fatty Liver; Gene Expression; Glycogen; Hepatitis B; Humans; Hyperplasia; Immunohistochemistry; Injections, Intraperitoneal; Lipid Metabolism; Liver; Polymerase Chain Reaction; Proliferating Cell Nuclear Antigen; Trans-Activators; Viral Regulatory and Accessory Proteins; Zebrafish

The glucokinase activators improve the fasting as well as postprandial glucose control and are important investigational drugs for the treatment of diabetes. However, recent studies have implicated that continuous activation of glucokinase with a small molecule activator can increase hepatic triglycerides and the long term glucose control is not achieved. In this study, we investigated the effect of combination of glucokinase activator (GKA, Piragliatin) with GLP-1 receptor agonist exendin-4 (Ex-4) in male db/db mice. Twelve weeks combination treatment in the db/db mice resulted in a significant decrease in body weight gain, food consumption, random glucose and %HbA1c. The decrease in serum glucose and %HbA1c in combination group was more profound and significantly different than that of individual treatment (GKA or Ex-4) group. GKA treatment increased hepatic triglycerides, whereas combination of Ex-4 with GKA attenuated hepatic steatosis. The combination of GKA with Ex-4 reduced the hepatic lipid accumulation, improved the insulin sensitivity, and reduced hepatic glucose production in db/db mice. Overall, our data indicate that combination of GKA and GLP-1 receptor agonist Ex-4 improves glucose homeostasis, shows antiobesity activity, without causing harmful side effects like fatty liver.

Topics: Animals; Benzeneacetamides; Body Weight; Drug Synergism; Eating; Enzyme Activation; Exenatide; Fatty Liver; Glucokinase; Glucose; Glycogen; Homeostasis; Hyperglycemia; Hypoglycemic Agents; Insulin; Insulin Resistance; Insulin Secretion; Islets of Langerhans; Liver; Male; Mice; Mice, Inbred C57BL; Peptides; Venoms

The physiological roles of the protease inhibitor SERPINB3 (SB3) are still largely unknown. The study was addressed to assess the biological effects of this serpin in vivo using a SB3 transgenic mouse model. Two colonies of mice (123 transgenic for SB3 and 148 C57BL/6J controls) have been studied. Transgenic (TG) mice showed longer survival than controls and the difference was more remarkable in males than in females (18.5% vs 12.7% life span increase). In TG mice decreased IL-6 in serum and lower p66shc in the liver were observed. In addition, TG males showed higher expression of mTOR in the liver. Liver histology showed age-dependent increase of steatosis and decrease of glycogen storage in both groups and none of the animals developed neoplastic lesions. In conclusion, the gain in life span observed in SB3-transgenic mice could be determined by multiple mechanisms, including the decrease of circulating IL-6 and the modulation of ageing genes in the liver.

Topics: Aging; Animals; Antigens, Neoplasm; Fatty Liver; Female; Glycogen; Hep G2 Cells; Humans; Interleukin-6; Liver; Longevity; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Protease Inhibitors; RNA, Messenger; Serpins; Shc Signaling Adaptor Proteins; Src Homology 2 Domain-Containing, Transforming Protein 1; TOR Serine-Threonine Kinases

Insulin resistance in Type 2 diabetes leads to hepatic steatosis that can accompanied by progressive inflammation of the liver. Citrus unshiu peel is a rich source of citrus flavonoids that possess anti-inflammatory, anti-diabetic and lipid-lowering effects. However, the ability of citrus unshiu peel ethanol extract (CPE) to improve hyperglycemia, adiposity and hepatic steatosis in Type 2 diabetes is unknown. Thus, we evaluated the effects of CPE on markers for glucose, lipid metabolism and inflammation in Type 2 diabetic mice. Male C57BL/KsJ-db/db mice were fed a normal diet with CPE (2 g/100 g diet) or rosiglitazone (0.001 g/100 g diet) for 6 weeks. Mice supplemented with the CPE showed a significant decrease in body weight gain, body fat mass and blood glucose level. The antihyperglycemic effect of CPE appeared to be partially mediated through the inhibition of hepatic gluconeogenic phosphoenolpyruvate carboxykinase mRNA expression and its activity and through the induction of insulin/glucagon secretion. CPE also ameliorated hepatic steatosis and hypertriglyceridemia via the inhibition of gene expression and activities of the lipogenic enzymes and the activation of fatty acid oxidation in the liver. These beneficial effects of CPE may be related to increased levels of anti-inflammatory adiponectin and interleukin (IL)-10, and decreased levels of pro-inflammatory markers (IL-6, monocyte chemotactic protein-1, interferon-γ and tumor necrosis factor-α) in the plasma or liver. Taken together, we suggest that CPE has the potential to improve both hyperglycemia and hepatic steatosis in Type 2 diabetes.

Topics: Adipose Tissue; Animals; Blood Glucose; Citrus; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Enzymes; Fatty Liver; Gene Expression Regulation; Glycogen; Hyperglycemia; Inflammation; Lipid Metabolism; Male; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Phosphoenolpyruvate Carboxykinase (ATP); Plant Extracts; Weight Gain

Air pollution is a global challenge to public health. Epidemiological studies have linked exposure to ambient particulate matter with aerodynamic diameters<2.5 μm (PM(2.5)) to the development of metabolic diseases. In this study, we investigated the effect of PM(2.5) exposure on liver pathogenesis and the mechanism by which ambient PM(2.5) modulates hepatic pathways and glucose homeostasis.. Using "Ohio's Air Pollution Exposure System for the Interrogation of Systemic Effects (OASIS)-1", we performed whole-body exposure of mice to concentrated ambient PM(2.5) for 3 or 10 weeks. Histological analyses, metabolic studies, as well as gene expression and molecular signal transduction analyses were performed to determine the effects and mechanisms by which PM(2.5) exposure promotes liver pathogenesis.. Mice exposed to PM(2.5) for 10 weeks developed a non-alcoholic steatohepatitis (NASH)-like phenotype, characterized by hepatic steatosis, inflammation, and fibrosis. After PM(2.5) exposure, mice displayed impaired hepatic glycogen storage, glucose intolerance, and insulin resistance. Further investigation revealed that exposure to PM(2.5) led to activation of inflammatory response pathways mediated through c-Jun N-terminal kinase (JNK), nuclear factor kappa B (NF-κB), and Toll-like receptor 4 (TLR4), but suppression of the insulin receptor substrate 1 (IRS1)-mediated signaling. Moreover, PM(2.5) exposure repressed expression of the peroxisome proliferator-activated receptor (PPAR)γ and PPARα in the liver.. Our study suggests that PM(2.5) exposure represents a significant "hit" that triggers a NASH-like phenotype and impairs hepatic glucose metabolism. The information from this work has important implications in our understanding of air pollution-associated metabolic disorders.

Topics: Animals; Disease Models, Animal; Fatty Liver; Glucose; Glucose Intolerance; Glycogen; Hepatitis; Homeostasis; Inhalation Exposure; Insulin; Insulin Receptor Substrate Proteins; Insulin Resistance; JNK Mitogen-Activated Protein Kinases; Liver; Liver Cirrhosis; Male; Mice; Mice, Inbred C57BL; NF-kappa B; Non-alcoholic Fatty Liver Disease; Particulate Matter; Phenotype; PPAR alpha; PPAR gamma; Signal Transduction; Toll-Like Receptor 4

Aging is closely associated with muscle insulin resistance, hyperlipidemia, nonalcoholic fatty liver disease (NAFLD), and type 2 diabetes. We examined the hypothesis that muscle insulin resistance in healthy aging promotes increased hepatic de novo lipogenesis (DNL) and hyperlipidemia by altering the distribution pattern of postprandial energy storage. Healthy, normal weight, sedentary elderly subjects pair-matched to young subjects were given two high-carbohydrate meals followed by ¹³C/¹H magnetic resonance spectroscopy measurements of postprandial changes in muscle and liver glycogen and lipid content, and assessment of DNL using ²H₂O. Net muscle glycogen synthesis was reduced by 45% (P < 0.007) in the elderly subjects compared with the young, reflecting severe muscle insulin resistance. Net liver glycogen synthesis was similar between groups (elderly, 143 ± 23 mmol/L vs. young, 138 ± 13 mmol/L; P = NS). Hepatic DNL was more than twofold higher in the elderly than in the young subjects (elderly, 14.5 ± 1.4% vs. young, 6.9 ± 0.7%; P = 0.00015) and was associated with approximately threefold higher postprandial hepatic triglyceride (TG) content (P < 0.005) and increased fasting plasma TGs (elderly, 1.19 ± 0.18 mmol/L vs. young, 0.74 ± 0.11 mmol/L; P = 0.02). These results strongly support the hypothesis that muscle insulin resistance in aging promotes hyperlipidemia and NAFLD by altering the pattern of postprandial carbohydrate storage away from muscle glycogen and into hepatic DNL.

Topics: Adult; Aged; Aging; Dietary Carbohydrates; Fatty Liver; Female; Glycogen; Humans; Hyperlipidemias; Insulin Resistance; Lipogenesis; Liver; Male; Metabolic Syndrome; Muscle, Skeletal; Non-alcoholic Fatty Liver Disease; Postprandial Period; Triglycerides; Young Adult

Persimmon Leaf (PL), commonly consumed as herbal tea and traditional medicines, contains a variety of compounds that exert antioxidant, α-amylase and α-glucosidase inhibitory activity. However, little is known about the in vivo effects and underlying mechanisms of PL on hyperglycemia, hyperlipidemia and hepatic steatosis in type 2 diabetes. Powered PL (5%, w/w) was supplemented with a normal diet to C57BL/KsJ-db/db mice for 5 weeks. PL decreased blood glucose, HOMA-IR, plasma triglyceride and total cholesterol levels, as well as liver weight, hepatic lipid droplets, triglycerides and cholesterol contents, while increasing plasma HDL-cholesterol and adiponectin levels. The anti-hyperglycemic effect was linked to decreased activity of gluconeogenic enzymes as well as increased glycogen content, glucokinase activity and its mRNA level in the liver. PL also led to a decrease in lipogenic transcriptional factor PPARγ as well as gene expression and activity of enzymes involved in lipogenesis, with a simultaneous increase in fecal lipids, which are seemingly attributable to the improved hyperlipidemia and hepatic steatosis and decreased hepatic fatty acid oxidation. Furthermore, PL ameliorated plasma and hepatic oxidative stress. Supplementation with PL may be an effective dietary strategy to improve type 2 diabetes accompanied by dyslipidemia and hepatic steatosis by partly modulating the activity or gene expression of enzymes related to antioxidant, glucose and lipid homeostasis.

Topics: Adiponectin; Animals; Antioxidants; Blood Glucose; Cholesterol; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Dietary Supplements; Diospyros; Dyslipidemias; Fatty Liver; Gene Expression; Glucokinase; Glycogen; Hyperglycemia; Hypoglycemic Agents; Insulin Resistance; Lipid Metabolism; Lipogenesis; Liver; Male; Mice; Mice, Inbred C57BL; Oxidative Stress; Phytotherapy; Plant Leaves; Plant Preparations; PPAR gamma; RNA, Messenger; Triglycerides

Oxidative damage to DNA is mainly repaired via base excision repair, a pathway that is catalyzed by DNA glycosylases such as 8-oxoguanine DNA glycosylase (OGG1). While OGG1 has been implicated in maintaining genomic integrity and preventing tumorigenesis, we report a novel role for OGG1 in altering cellular and whole body energy homeostasis. OGG1-deficient (Ogg1(-/-)) mice have increased adiposity and hepatic steatosis following exposure to a high-fat diet (HFD), compared to wild-type (WT) animals. Ogg1(-/-) animals also have higher plasma insulin levels and impaired glucose tolerance upon HFD feeding, relative to WT counterparts. Analysis of energy expenditure revealed that HFD-fed Ogg1(-/-) mice have a higher resting VCO(2) and consequently, an increased respiratory quotient during the resting phase, indicating a preference for carbohydrate metabolism over fat oxidation in these mice. Additionally, microarray and quantitative PCR analyses revealed that key genes of fatty acid oxidation, including carnitine palmitoyl transferase-1, and the integral transcriptional co-activator Pgc-1α were significantly downregulated in Ogg1(-/-) livers. Multiple genes involved in TCA cycle metabolism were also significantly reduced in livers of Ogg1(-/-) mice. Furthermore, hepatic glycogen stores were diminished, and fasting plasma ketones were significantly reduced in Ogg1(-/-) mice. Collectively, these data indicate that OGG1 deficiency alters cellular substrate metabolism, favoring a fat sparing phenotype, that results in increased susceptibility to obesity and related pathologies in Ogg1(-/-) mice.

Topics: Adiposity; Animals; Diet, High-Fat; DNA Glycosylases; DNA, Mitochondrial; Energy Metabolism; Fatty Liver; Glucose; Glucose Tolerance Test; Glycogen; Insulin; Lipids; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Obesity; Oxidative Stress

Recent extensive studies have revealed that molecular hydrogen (H(2)) has great potential for improving oxidative stress-related diseases by inhaling H(2) gas, injecting saline with dissolved H(2), or drinking water with dissolved H(2) (H(2)-water); however, little is known about the dynamic movement of H(2) in a body. First, we show that hepatic glycogen accumulates H(2) after oral administration of H(2)-water, explaining why consumption of even a small amount of H(2) over a short span time efficiently improves various disease models. This finding was supported by an in vitro experiment in which glycogen solution maintained H(2). Next, we examined the benefit of ad libitum drinking H(2)-water to type 2 diabetes using db/db obesity model mice lacking the functional leptin receptor. Drinking H(2)-water reduced hepatic oxidative stress, and significantly alleviated fatty liver in db/db mice as well as high fat-diet-induced fatty liver in wild-type mice. Long-term drinking H(2)-water significantly controlled fat and body weights, despite no increase in consumption of diet and water. Moreover, drinking H(2)-water decreased levels of plasma glucose, insulin, and triglyceride, the effect of which on hyperglycemia was similar to diet restriction. To examine how drinking H(2)-water improves obesity and metabolic parameters at the molecular level, we examined gene-expression profiles, and found enhanced expression of a hepatic hormone, fibroblast growth factor 21 (FGF21), which functions to enhance fatty acid and glucose expenditure. Indeed, H(2) stimulated energy metabolism as measured by oxygen consumption. The present results suggest the potential benefit of H(2) in improving obesity, diabetes, and metabolic syndrome.

Topics: Animals; Diabetes Mellitus, Type 2; Energy Metabolism; Fatty Liver; Fibroblast Growth Factors; Glycogen; Hydrogen; Hyperglycemia; Liver; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Oxidative Stress; Random Allocation; Rats; Rats, Sprague-Dawley; RNA, Messenger; Water

To determine whether the phosphoinositide 3-kinase (PI3K) catalytic subunits p110-α and p110-β play a role in liver steatosis induced by a high-fat diet (HFD).. Liver-specific p110-α and p110-β knockout mice and control animals for each group were fed an HFD or normal chow for 8 weeks. Biochemical assays and quantitative real-time PCR were used to measure triglyceride, expression of lipogenic and gluconeogenic genes, and activity of protein kinases downstream of PI3K in liver lysates. Fatty acid uptake and incorporation into triglycerides were assessed in isolated hepatocytes.. Hepatic triglyceride levels in HFD-fed p110-α(-/-) mice were 84 ± 3% lower than in p110-α(+/+) mice, whereas the loss of p110-β did not significantly alter liver lipid accumulation. p110-α(-/-) livers also showed a reduction in atypical protein kinase C activity and decreased mRNA and protein expression of several lipogenic genes. Hepatocytes isolated from p110-α(-/-) mice exhibited decreased palmitate uptake and reduced fatty acid incorporation into triglycerides as compared with p110-α(+/+) cells, and hepatic expression of liver fatty acid binding protein was lower in p110-α(-/-) mice fed the HFD as compared with controls. Ablation of neither p110-α nor p110-β ameliorated glucose intolerance induced by the HFD, and genes involved in gluconeogenesis were upregulated in the liver of both knockout animals.. PI3K p110-α, and not p110-β, promotes liver steatosis in mice fed an HFD. p110-α might exert this effect in part through activation of atypical protein kinase C, upregulation of lipogenesis, and increased uptake of fatty acids.

Topics: Animals; Blotting, Western; Cells, Cultured; Class I Phosphatidylinositol 3-Kinases; Dietary Fats; Fatty Liver; Glucose Tolerance Test; Glycogen; Insulin; Liver; Mice; Mice, Knockout; Phosphatidylinositol 3-Kinases; Reverse Transcriptase Polymerase Chain Reaction

Non-alcoholic fatty liver disease (NAFLD) is associated with hepatic insulin resistance with the molecular basis of this association being not well understood. Here we studied the effect of hepatic triglyceride accumulation induced by postprandial triglyceride-rich lipoproteins (TGRL) on hepatic insulin sensitivity in HepG2 cells. Incubation of HepG2 cells with purified TGRL particles induced hepatocellular triglyceride accumulation paralleled by diminished insulin-stimulated glycogen content and glycogen synthase activity. Accordingly, insulin-induced inhibition of glycogen synthase phosphorylation as well as insulin-induced GSK-3 and AKT phosphorylation were reduced by TGRL. The effects of TGRL were dependent on the presence of apolipoproteins and more pronounced for denser TGRL. Moreover, TGRL effects required the presence of heparan sulfate-proteoglycans on the cell membrane and lipase activity but were independent of the cellular uptake of TGRL particles by receptors of the LDL receptor family. We suggest postprandial lipemia to be an important factor in the pathogenesis of NAFLD.

Topics: Adult; Fatty Liver; Glycogen; Glycogen Synthase; Glycogen Synthase Kinase 3; Hep G2 Cells; Humans; Hypertriglyceridemia; Insulin Resistance; Lipoproteins; Liver; Male; Non-alcoholic Fatty Liver Disease; Postprandial Period; Proto-Oncogene Proteins c-akt; Receptors, LDL; Triglycerides

Rubratoxin B is a mycotoxin that causes hypoglycemia and fatty liver. We investigated the effect of rubratoxin B on hepatic glycogen content and regulation, because blood glucose levels are associated with hepatic glycogen storage. Mice were treated with 1.5mg/kg rubratoxin B for 24h. Stomachs of treated mice became extremely swollen, and the contents were significantly heavier than those of controls. Hypoglycemia stimulates appetite; therefore, rubratoxin B may perturb satiation. Rubratoxin B evidently depleted hepatic glycogen stores. Phosphoenolpyruvate carboxykinase (PEPCK) activity and mRNA levels in treated mice were reduced, indicating that rubratoxin B caused hepatic glycogen depletion by inhibiting PEPCK. PEPCK activity and mRNA levels were reduced to similar degrees; it appears that PEPCK activity is regulated transcriptionally. Levels of the PEPCK gene trans-activators phospho-CREB (active form) and C/EBPα were significantly reduced in the livers of treated mice, suggesting that these factors are important for PEPCK gene transcription. Rubratoxicosis and fatty acid oxidation disorders (FAODs) share characteristic signs, such as robust appetite, hypoglycemia, hepatic glycogen depletion, and fatty liver. Although FAODs are generally considered genetic deficiencies, our results indicate that a chemical can also cause FAOD-like signs in mice.

Topics: Animals; Appetite Regulation; CCAAT-Enhancer-Binding Protein-alpha; Cyclic AMP Response Element-Binding Protein; Disease Models, Animal; Fatty Acids; Fatty Liver; Gastric Dilatation; Gene Expression Regulation, Enzymologic; Glycogen; Lipid Metabolism Disorders; Liver; Male; Mice; Mice, Inbred C3H; Mycotoxins; Oxidation-Reduction; Phosphoenolpyruvate Carboxykinase (GTP); Phosphorylation; Protein Processing, Post-Translational; RNA, Messenger; Specific Pathogen-Free Organisms

Shiitake mushrooms (SMs) have been used in Asia for treatment and/or prevention of chronic diseases and hypercholesterolemia. Previously, we observed a diet supplemented with 5% SM resulted in a twofold increase in plasma IL-6 levels in DBA arthritic mice. An elevation in plasma IL-6 has also been implicated in the pathogenesis fatty liver disease. Thus, the aim of this study was to investigate the effect of SM supplemented-diet on hepatic steatosis. In study 1, eight-week old female C57BL/6 mice were randomly assigned to the following groups for 6 weeks: the AIN-93 diet; 5% SM, and 5% white button mushroom (WBM) supplemented diets (12/group). In study 2, mice were fed either the AIN-93 diet or SM (20/group). After 6 weeks, 13 mice fed SM diet were given the AIN93 diet for 8 or 15 days. Unlike other groups, all mice fed the SM diet developed fatty liver (mean histopathology score 4.5 vs <1 in the other groups; p<0.001) without fibrosis and inflammation. Fifteen days post withdrawal of SM completely normalized liver histology. To the best of our knowledge, this is the first report that chronic consumption of SM is associated with the development of fatty liver. The mechanism by which SM causes hepatic steatosis warrants further investigation.

Topics: Aflatoxins; Agaricus; Animals; Asia; Body Weight; Diet; Dietary Supplements; Endotoxins; Fatty Liver; Female; Glycogen; Interleukin-6; Liver; Mice; Mice, Inbred C57BL; Organ Size; Shiitake Mushrooms

Sinigrin (SIN) and allyl isothiocyanate (AITC) are compounds found in high concentrations in Brassica family vegetables, especially in Brussels sprouts. Recently, they have been used as a nutrition supplement for their preventive and medicinal effect on some types of cancer and other diseases. In this research, nutritional significance of parent glucosinolate sinigrin 50 μmol/kg b. w./day and its degradation product allyl isothiocyanate 25 μmol/kg b. w./day and 50 μmol/kg b. w./day was studied by the evaluation of their influence on some parameters of carbohydrate and lipid metabolism in an animal rat model in vivo after their single (4 h) and 2 weeks oral administration. Additionally, the aim of this trial was to evaluate the direct action of AITC on basal and epinephrine-induced lipolysis in isolated rat adipocytes at concentration 1 μM, 10 μM and 100 μM in vitro. Sole AITC after 4 h of its ingestion caused liver triacylglycerols increment at both doses and glycaemia only at the higher dose. Multiple SIN treatment showed its putative bioconversion into AITC. It was found that SIN and AITC multiple administration in the same way strongly disturbed lipid and carbohydrate homeostasis, increasing esterified and total cholesterol, free fatty acids and lowering tracylglycerols in the blood serum. Additionally, AITC at both doses elevated insulinaemia and liver glycogen enhancement. The in vitro experiment revealed that AITC potentiated basal lipolysis process at 10 μM, and had stimulatory effect on epinephrine action at 1 μM and 10 μM. The results of this study demonstrated that the effect of SIN and AITC is multidirectional, indicating its impact on many organs like liver as well as pancreas, intestine in vivo action and rat adipocytes in vitro. Whilst consumption of cruciferous vegetables at levels currently considered "normal" seems to be beneficial to human health, this data suggest that any large increase in intake could conceivably lead to undesirable effect. This effect is potentiated with time of action of the examined compounds, whose influence is rather adverse for the majority of metabolic pathways (liver steatosis at short duration and insulinaemia, cholesterolaemia at long time treatment). Beneficial action of AITC concerned intensified hydrolysis of TG in the blood serum with a simultaneous lipolysis in adipocytes.

Topics: Adipocytes; Animals; Brassica; Carbohydrate Metabolism; Cholesterol; Dose-Response Relationship, Drug; Epinephrine; Esterification; Fatty Acids, Nonesterified; Fatty Liver; Glucosinolates; Glycogen; Homeostasis; Hydrolysis; Hyperinsulinism; Isothiocyanates; Lipid Metabolism; Lipolysis; Liver; Male; Models, Animal; Pancreas; Rats; Rats, Wistar; Time Factors; Triglycerides

We tested whether rat liver preservation performed by machine perfusion (MP) at 20 degrees C can enhance the functional integrity of steatotic livers versus simple cold storage. We also compared MP at 20 degrees C with hypothermic MP at 8 degrees C, and 4 degrees C. Obese and lean male Zucker rats were used as liver donors. MP was performed for 6 hours with a glucose and N-acetylcysteine-supplemented Krebs-Henseleit solution. Both MP and cold storage preserved livers were reperfused with Krebs-Henseleit solution (2 hours at 37 degrees C). MP at 4 degrees C and 8 degrees C reduced the fatty liver necrosis compared with cold storage but we further protected the organs using MP at 20 degrees C. Necrosis did not differ in livers from lean animals submitted to the different procedures; the enzymes released in steatotic livers preserved by MP at 20 degrees C were similar to those showed in nonsteatotic organs. The adenosine triphosphate/adenosine diphosphate ratio and bile production were higher and the oxidative stress and biliary enzymes were lower in steatotic livers preserved by MP at 20 degrees C as compared with cold storage. In livers from lean rats, the adenosine triphosphate/adenosine diphosphate ratio appears better conserved by MP at 20 degrees C as compared with cold storage. In steatotic livers preserved by cold storage, a 2-fold increase in tumor necrosis factor-alpha levels and caspase-3 activity was observed as compared with organs preserved by MP at 20 degrees C. These data are substantiated by better morphology, higher glycogen content, and lower reactive oxygen species production by sinusoidal cells in steatotic liver submitted to MP at 20 degrees C versus cold storage. MP at 20 degrees C improves cell survival and leads to a marked improvement in hepatic preservation of steatotic livers as compared with cold storage.

Topics: Acetylcysteine; Animals; Bile; Cell Survival; Fatty Liver; Glucose; Glycogen; Liver; Male; Organ Preservation; Perfusion; Rats; Rats, Zucker; Reactive Oxygen Species; Temperature; Tissue Donors

The high consumption of fructose leads to the increasing incidence of insulin resistance by several unknown mechanisms. Hepatic glucose metabolism may also be an important target of fructose-induced-metabolic alterations.. The aim of present study was to investigate alterations in hepatic glycogenolysis, glycogenesis and gluconeogenic fluxes by feeding of 21% high fructose diet and the effects of Rosiglitazone treatment to prevent these derangements in rats.. Rats were maintained on normal chow and high fructose diet with or without Rosiglitazone for 8 weeks and various biochemical and gene expression measures were estimated.. The feeding of high fructose diet impaired glucose, insulin and pyruvate tolerance tests and increased blood HbA(1c), insulin, triglyceride, free fatty acids and homeostasis model assessment after 8 weeks. In addition, high fructose diet feeding increased expression of phosphoenol-pyruvatecorboxykinase, glucose-6-phosphatase, sterol regulatory element binding proteins-1 and fatty acid synthase through enhanced expression of fork-head receptor, peroxisome proliferator activated receptor-gamma-co-activator 1 and cAMP reactive element binding protein. The treatment with Rosiglitazone inhibited all these derangements, i.e. hepato-lipogenic and gluconeogenic effects of high fructose diet feeding in rats.. Together these findings suggest that high fructose diet induced hepatic gluconeogenic and lipogenic rate, and increased circulating triglycerides and free fatty acids, which may be the major risk factors for glucose intolerance, hyperglycemia and insulin resistance in rats. In such situations high fructose flux also induces transcriptional cascade of gluconeogenic enzymes through the modulation of various associated transcriptional factors.

Topics: Animals; Epigenesis, Genetic; Fatty Liver; Fructose; Gluconeogenesis; Glucose Metabolism Disorders; Glycogen; Hypoglycemic Agents; Male; Rats; Rosiglitazone; Sweetening Agents; Thiazolidinediones

We isolated several stilbene compounds including rhaponticin (3',5-dihydroxy-4'-methoxystilbene 3- O-beta- D-glucopyranoside) from extracts of rhubarb rhizomes. These compounds showed significant hypoglycemic effects in streptozotocin (STZ)-induced type 1 diabetic rats and mice. In this study, we investigated the effect of rhaponticin on glucose utilization, lipid metabolism, and liver and heart function in a KK/Ay type 2 diabetic mouse model. The results showed that oral administration of rhaponticin (125 mg/kg) significantly reduced blood glucose levels and improved oral glucose tolerance of KK/Ay diabetic mice. Elevated plasma triglyceride (TG), low density lipoprotein (LDL), cholesterol (CHO), non-esterified free fatty acids (NEFA), and insulin levels were also markedly attenuated. Serum enzymatic activities of lactate dehydrogenase (LDH), creatine kinase (CK), aspartate aminotransferase (AST), and alanine aminotransferase (ALT) in the rhaponticin-treated group significantly decreased in comparison to the untreated model group. Livers of rhaponticin-treated mice had relatively normal cellular size and decreased fibrosis and steatosis. In addition, rhaponticin administration caused a remarkable increase in the hepatic glycogen content and a significant reduction in the hepatic triglyceride content. These results indicate that rhaponticin has a noticeable antidiabetic effect and could be potentially used as a new agent to treat type 2 diabetes mellitus and its complications.

Topics: Animals; Blood Glucose; Cholesterol; Diabetes Mellitus, Experimental; Enzymes; Fatty Acids, Nonesterified; Fatty Liver; Glucose Tolerance Test; Glycogen; Hypoglycemic Agents; Insulin; Lipids; Lipoproteins, LDL; Liver; Mice; Rheum; Rhizome; Stilbenes; Triglycerides

Low levels of melatonin in circulation had been reported to be related to the development of diabetes. Melatonin administration in animals increases hepatic glycogen content to lower blood glucose. However, the signaling pathway for these effects is still unclear. The present study shows that intraperitoneal injection of 10 mg/kg melatonin ameliorated glucose utilization and insulin sensitivity in high fat diet-induced diabetic mice with an increase in hepatic glycogen and improvement in liver steatosis. We used HepG2 cells to investigate the signaling pathways for the melatonin-stimulated hepatic glycogen increment. Treatment of HepG2 cells with 1 nm melatonin markedly increased glycogen synthesis which was blocked by the melatonin receptor antagonist luzindole. In addition, melatonin increased the phosphorylation of subcellular signals at the level of protein kinase C zeta (PKCzeta), Akt, and glycogen synthase kinase 3beta (GSK3beta) while the increase in glycogen synthesis induced by melatonin was inhibited by PKCzeta pseudo-peptide. However, 3',5'-cyclic adenosine monophosphate-activated protein kinase (AMPK) was not influenced by melatonin treatment. Taken together, melatonin improves glucose intolerance and insulin resistance in high fat diet-induced diabetic mice and stimulates glycogen synthesis via a PKCzeta-Akt-GSK3beta pathway in HepG2 cells.

Topics: Animals; Antioxidants; Blotting, Western; Cell Line, Tumor; Diabetes Mellitus, Experimental; Dietary Fats; Fatty Liver; Glycogen; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Male; Melatonin; Mice; Mice, Inbred C57BL; Phosphorylation; Protein Kinase C; Proto-Oncogene Proteins c-akt; Signal Transduction

Exercise training is commonly prescribed for treatment of nonalcoholic fatty liver disease (NAFLD). We sought to determine whether exercise training prevents the development of NAFLD in Otsuka Long-Evans Tokushima Fatty (OLETF) rats and to elucidate the molecular mechanisms underlying the effects of exercise on hepatic steatosis. Four-week-old OLETF rats were randomly assigned to either a sedentary control group (Sed) or a group given access to voluntary running wheels for 16 wk (Ex). Wheels were locked 2 days before euthanasia in the Ex animals, and both groups were euthanized at 20 wk old. Voluntary wheel running attenuated weight gain and reduced serum glucose, insulin, free fatty acids, and triglycerides in Ex animals compared with Sed (P < 0.001). Ex animals exhibited significantly reduced hepatic triglyceride levels and displayed fewer lipid droplets (Oil Red O staining) and reduced lipid droplet size compared with Sed. Wheel running increased by threefold the percent of palmitate oxidized completely to CO(2) in the Ex animals but did not alter AMP-activated protein kinase-alpha (AMPKalpha) or AMPK phosphorylation status. However, fatty acid synthase and acetyl-coenzyme A carboxylase (ACC) content were significantly reduced (approximately 70 and approximately 35%, respectively), and ACC phosphorylation and cytochrome c content were significantly elevated (approximately 35 and approximately 30%, respectively) in the Ex animals. These results unequivocally demonstrate that daily physical activity attenuates hepatic steatosis and NAFLD in an obese rodent model and suggest that this effect is likely mediated, in part, through enhancement of hepatic fatty acid oxidation and reductions in key protein intermediates of fatty acid synthesis.

Topics: 3-Hydroxyacyl CoA Dehydrogenases; Acetyl-CoA Carboxylase; Adipose Tissue; Animals; Azo Compounds; Blotting, Western; Citrate (si)-Synthase; Coloring Agents; Fatty Acid Synthases; Fatty Acids; Fatty Liver; Glycogen; Liver; Oxidation-Reduction; Physical Conditioning, Animal; Rats; Rats, Inbred OLETF

Juvenile visceral steatosis (jvs-/-) mice lack the activity of the carnitine transporter OCTN2 and are dependent on carnitine substitution. The effects of carnitine deprivation on carnitine homeostasis and energy metabolism are not known in jvs-/- mice.. jvs-/- mice were studied 3, 6 and 10 days after carnitine deprivation, and compared to jvs-/- mice substituted with carnitine, wild-type (jvs+/+) and jvs+/- mice. Carnitine concentrations were assessed radioenzymatically.. Compared to wild-type mice, carnitine-treated jvs-/- mice had decreased plasma beta-hydroxybutyrate levels and showed hepatic fat accumulation. The carnitine levels in plasma, liver and skeletal muscle were decreased by 58, 16 and 17%, respectively. After ten days of carnitine deprivation, the plasma carnitine concentration had fallen by 87% (to 2.3 mumol/l) and the tissue carnitine levels by approximately 50% compared to carnitine-treated jvs-/- mice. Carnitine deprivation was associated with a further drop in plasma beta-hydroxybutyrate and increased hepatic fat. Skeletal muscle glycogen stores decreased and lactate levels increased with carnitine deprivation, whereas tissue ATP levels were maintained.. In jvs-/- mice, tissue carnitine stores are more resistant than carnitine plasma concentrations to carnitine deprivation. Metabolic changes (liver steatosis and loss of muscle glycogen stores) appear also early after carnitine deprivation.

Topics: 3-Hydroxybutyric Acid; Adenosine Triphosphate; Animals; Body Weight; Carnitine; Energy Metabolism; Fatty Liver; Genotype; Glycogen; Homeostasis; Lactates; Lipid Metabolism, Inborn Errors; Liver; Mice; Mice, Knockout; Muscle, Skeletal; Organ Size; Organic Cation Transport Proteins; Solute Carrier Family 22 Member 5

Studies have revealed that high-fat (HF) diets promote hyperglycaemia, whole-body insulin resistance and non-alcoholic fatty liver disease (NAFLD). Recently, hepatic glucagon resistance has been shown to occur in rats fed a HF diet. More precisely, diet-induced obesity (DIO) reduces the number of hepatic plasma membrane glucagon receptors (GR), which results in a diminished response to glucagon during a hyperglucagonaemic clamp. The present study was undertaken to test the hypothesis that a HF-DIO is associated with a desensitization and destruction of the hepatic GR. We also hypothesized that a single bout of endurance exercise would modify the GR cellular distribution under our DIO model. Male rats were either fed a standard (SD) or a HF diet for two weeks. Each group was subdivided into a non-exercised (Rest) and an acute exercised (EX) group. The HF diet resulted in a reduction of total hepatic GR (55%) and hepatic plasma membrane GR protein content (20%). These changes were accompanied by a significant increase in endosomal and lysosomal GR content with the feeding of a HF diet. The reduction of GR plasma membrane as well as the increase in endosomal GR was strongly correlated with an increase of PKC-alpha, suggesting a role of PKC-alpha in GR desensitization. EX increased significantly PKC-alpha protein content in both diets, suggesting a role of PKC-alpha in EX-induced GR desensitization. The present results suggest that liver lipid infiltration plays a role in reducing glucagon action in the liver through a reduction in total cellular and plasma membrane GR content. Furthermore, the GR desensitization observed in our in vivo model of HF diet-induced hepatic steatosis and in EX individuals may be regulated by PKC-alpha.

Topics: Animals; beta-Adrenergic Receptor Kinases; Cell Membrane; Dietary Fats; Endosomes; Fatty Liver; G-Protein-Coupled Receptor Kinase 2; Glycogen; Hepatocytes; Hyperglycemia; Lysosomes; Male; Obesity; Physical Exertion; Protein Kinase C-alpha; Rats; Rats, Sprague-Dawley; Receptors, Glucagon; Triglycerides

Thyroid hormone regulates the balance between lipolysis and lipogenesis. We previously reported that male mice with a dominant-negative P398H mutation introduced into the TRalpha gene have visceral obesity, hyperleptinemia, and reduced catecholamine-stimulated lipolysis in white adipose tissue. Based on our observation of hepatic steatosis in the TRalpha P398H male mice, we used in vitro and in vivo models to investigate the influence of the TRalpha P398H mutant on peroxisome proliferator-activated receptor-alpha (PPARalpha) signaling. Wild-type TRalpha and the P398H mutant significantly reduced PPARalpha-mediated transcription in transient transfection assays. T(3) reversed the inhibition of PPARalpha action by wild-type TRalpha but not the P398H mutant. Chromatin immunoprecipitation assays demonstrated that the P398H mutant reduces PPARalpha binding to peroxisome proliferator receptor elements. In gel shift assays, the P398H mutant directly bound the peroxisome proliferator-activated receptor response element and inhibited PPARalpha binding, which was not reversed by addition of retinoid X receptor. The TRalpha R384C and PV dominant-negative mutants are not associated in vivo with a metabolic phenotype and had reduced (PV) or absent (R384C) PPARalpha inhibition compared with P398H. The metabolic phenotype of the P398H mutant mice is due, in part, to unique properties of the P398H mutant receptor interfering with PPARalpha signaling. The P398H mutant is a potential probe to characterize the physiological role of thyroid hormone receptor/PPARalpha interactions.

Topics: Animals; Fatty Acids; Fatty Liver; Glycogen; Lipid Metabolism; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mutant Proteins; Oxidation-Reduction; PPAR alpha; Regulatory Elements, Transcriptional; Signal Transduction; Thyroid Hormone Receptors alpha; Transcriptional Activation

This study tested whether hepatic steatosis sensitizes liver to toxicant-induced injury and investigated the potential mechanisms of hepatotoxic sensitivity. Male Sprague-Dawley rats were fed a methionine- and choline-deficient diet for 31 days to induce steatosis. On the 32nd day, administration of a nonlethal dose of CCl4 (2 mL/kg, intraperitoneally) yielded 70% mortality in steatotic rats 12-72 hours after CCl4 administration, whereas all nonsteatotic rats survived. Neither CYP2E1 levels nor covalent binding of [14C] CCl4-derived radio-label differed between the groups, suggesting that increased bioactivation is not the mechanism for this amplified toxicity. Cell division and tissue repair, assessed by [3H]thymidine incorporation and proliferative cell nuclear antigen assay, were inhibited in the steatotic livers after CCl4 administration and led to progressive expansion of liver injury culminating in mortality. The hypothesis that fatty hepatocytes undergo cell cycle arrest due to (1) an inability to replenish ATP due to overexpressed uncoupling protein-2 (UCP-2) or (2) induction of growth inhibitor p21 leading to G1/S phase arrest was tested. Steatotic livers showed 10-fold lower ATP levels due to upregulated UCP-2 throughout the time course after CCl4 administration, leading to sustained inhibition of cell division. Western blot analysis revealed an up-regulation of p21 due to overexpression of TGF beta1 and p53 and down-regulation of transcription factor Foxm 1b in steatotic livers leading to lower phosphorylated retinoblastoma protein. Thus, fatty hepatocytes fail to undergo compensatory cell division, rendering the liver susceptible to progression of liver injury.. Impaired tissue repair sensitizes the steatotic livers to hepatotoxicity.

Topics: Adenosine Triphosphate; Animals; Carbon Tetrachloride; Cell Cycle; Cell Division; Cyclin-Dependent Kinase Inhibitor p21; Cytochrome P-450 CYP2E1; DNA; Drug Tolerance; Fatty Liver; Glycogen; Hepatocytes; Ion Channels; Lipid Peroxidation; Liver; Male; Mitochondrial Proteins; Proliferating Cell Nuclear Antigen; Rats; Rats, Sprague-Dawley; Uncoupling Protein 2

Fatty liver is commonly associated with insulin resistance and type 2 diabetes, but it is unclear whether triacylglycerol accumulation or an excess flux of lipid intermediates in the pathway of triacyglycerol synthesis are sufficient to cause insulin resistance in the absence of genetic or diet-induced obesity. To determine whether increased glycerolipid flux can, by itself, cause hepatic insulin resistance, we used an adenoviral construct to overexpress glycerol-sn-3-phosphate acyltransferase-1 (Ad-GPAT1), the committed step in de novo triacylglycerol synthesis. After 5-7 days, food intake, body weight, and fat pad weight did not differ between Ad-GPAT1 and Ad-enhanced green fluorescent protein control rats, but the chow-fed Ad-GPAT1 rats developed fatty liver, hyperlipidemia, and insulin resistance. Liver was the predominant site of insulin resistance; Ad-GPAT1 rats had 2.5-fold higher hepatic glucose output than controls during a hyperinsulinemic-euglycemic clamp. Hepatic diacylglycerol and lysophosphatidate were elevated in Ad-GPAT1 rats, suggesting a role for these lipid metabolites in the development of hepatic insulin resistance, and hepatic protein kinase Cepsilon was activated, providing a potential mechanism for insulin resistance. Ad-GPAT1-treated rats had 50% lower hepatic NF-kappaB activity and no difference in expression of tumor necrosis factor-alpha and interleukin-beta, consistent with hepatic insulin resistance in the absence of increased hepatic inflammation. Glycogen synthesis and uptake of 2-deoxyglucose were reduced in skeletal muscle, suggesting mild peripheral insulin resistance associated with a higher content of skeletal muscle triacylglycerol. These results indicate that increased flux through the pathway of hepatic de novo triacylglycerol synthesis can cause hepatic and systemic insulin resistance in the absence of obesity or a lipogenic diet.

Topics: Adenoviridae; Animals; Deoxyglucose; Fatty Liver; Gene Expression; Glycerol-3-Phosphate O-Acyltransferase; Glycogen; Hyperlipidemias; Insulin Resistance; Interleukin-1beta; Lipid Metabolism; Liver; Male; Muscle, Skeletal; NF-kappa B; Protein Kinase C-epsilon; Rats; Rats, Wistar; Transduction, Genetic; Triglycerides; Tumor Necrosis Factor-alpha

Aqueous extract of the fruits of Solanum xanthocarpum Schrad. & Wendl. (Solanaceae) was investigated for hypoglycaemic activity in rats and mice. Screening for the hypoglycaemic activity was assessed on normoglycaemic, alloxan treated hyperglycaemic and glucose loaded rats along with in vitro study on glucose utilization by isolated rat hemidiaphragm. The various haematological and biochemical parameters were also studied. The extract was found to possess significant hypoglycaemic activity when compared with the reference standard glibenclamide. The in vitro study on glucose utilization by isolated rat hemidiaphragm suggests that the aqueous extract may have direct insulin like activity which enhances the peripheral utilization of glucose and have extra pancreatic effect. The toxicity studies report safety usage of the plant extract.

Topics: Alloxan; Animals; Blood Glucose; Cholesterol, VLDL; Diabetes Mellitus, Experimental; Diaphragm; Fatty Liver; Fruit; Glyburide; Glycogen; Hypoglycemic Agents; India; Kidney; Lipoproteins, HDL; Liver; Medicine, Traditional; Mice; Necrosis; Plant Extracts; Rats; Rats, Wistar; Solanaceae; Triglycerides; Water; Weight Loss

Obesity is a metabolic disorder often associated with type 2 diabetes, insulin resistance, and hepatic steatosis. Leptin-deficient (ob/ob) mice are a well-characterized mouse model of obesity in which increased hepatic lipogenesis is thought to be responsible for the phenotype of insulin resistance. We have recently demonstrated that carbohydrate responsive element-binding protein (ChREBP) plays a key role in the control of lipogenesis through the transcriptional regulation of lipogenic genes, including acetyl-CoA carboxylase and fatty acid synthase. The present study reveals that ChREBP gene expression and ChREBP nuclear protein content are significantly increased in liver of ob/ob mice. To explore the involvement of ChREBP in the physiopathology of hepatic steatosis and insulin resistance, we have developed an adenovirus-mediated RNA interference technique in which short hairpin RNAs (shRNAs) were used to inhibit ChREBP expression in vivo. Liver-specific inhibition of ChREBP in ob/ob mice markedly improved hepatic steatosis by specifically decreasing lipogenic rates. Correction of hepatic steatosis also led to decreased levels of plasma triglycerides and nonesterified fatty acids. As a consequence, insulin signaling was improved in liver, skeletal muscles, and white adipose tissue, and overall glucose tolerance and insulin sensitivity were restored in ob/ob mice after a 7-day treatment with the recombinant adenovirus expressing shRNA against ChREBP. Taken together, our results demonstrate that ChREBP is central for the regulation of lipogenesis in vivo and plays a determinant role in the development of the hepatic steatosis and of insulin resistance in ob/ob mice.

Topics: Adipose Tissue; Animals; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; Blood Glucose; Dietary Carbohydrates; Down-Regulation; Fatty Acids, Nonesterified; Fatty Liver; Glucose; Glucose Tolerance Test; Glycogen; Insulin; Insulin Resistance; Leptin; Lipids; Liver; Male; Mice; Mice, Obese; Muscle, Skeletal; Nuclear Proteins; Obesity; RNA, Messenger; RNA, Small Interfering; Signal Transduction; Transcription Factors; Transfection; Triglycerides

Fatty liver is a common feature of both obesity and lipodystrophy, reflecting compromised adipose tissue function. The lipin-deficient fatty liver dystrophy (fld) mouse is an exception, as there is lipodystrophy without a fatty liver. Using a combination of indirect calorimetry and stable-isotope flux phenotyping, we determined that fld mice exhibit abnormal fuel utilization throughout the diurnal cycle, with increased glucose oxidation near the end of the fasting period and increased fatty acid oxidation during the feeding period. The mechanisms underlying these alterations include a twofold increase compared with wild-type mice in tissue glycogen storage during the fed state, a 40% reduction in hepatic glucose production in the fasted state, and a 27-fold increase in de novo fatty acid synthesis in liver during the fed state. Thus, the inability to store energy in adipose tissue in the fld mouse leads to a compensatory increase in glycogen storage for use during the fasting period and reliance upon hepatic fatty acid synthesis to provide fuel for peripheral tissues during the fed state. The increase in hepatic fatty acid synthesis and peripheral utilization provides a potential mechanism to ameliorate fatty liver in the fld that would otherwise occur as a consequence of adipose tissue dysfunction.

Topics: Animals; Base Sequence; Calorimetry, Indirect; Circadian Rhythm; DNA Primers; Energy Metabolism; Fatty Acid Synthases; Fatty Liver; Glycogen; Liver; Mice; Mice, Inbred BALB C; Mice, Knockout; Nuclear Proteins; Phosphatidate Phosphatase

Microcirculation disturbances are essential factors of preservation injury in fatty liver. However, hepatocyte injury is also markedly excessive in fatty liver resulting, at least in part, from energy metabolism impairment and oxidative stress. Thus, this study aimed to determine whether nutritional status influences preservation injury in fatty liver and whether energetic substrate supplementation, alone or with a vasodilator, is protective.. Normal or fatty livers induced by a choline-deficient diet were isolated from fed and fasted rats, preserved in University of Wisconsin solution at 4 degrees C for 18 h, and then reperfused with Krebs-Henseleit solution at 37 degrees C for 120 min. Fasted rats with fatty liver were also treated as follows: (1) Glucose supplementation: rats had access to a glucose solution for 18 h prior procurement; (2) Prostaglandin (PG): alprostadil was continuously infused during reperfusion; (3) Combined treatment: Glucose supplementation + PG.. Fasting-induced liver injury was significantly greater in fatty than normal liver. In fatty livers from fasted rats, all treatments reduced the alanine aminotransaminase release. Hepatic oxygen consumption improved in the glucose and glucose + PG groups, while PG infusion had no effect. Glucose supplementation did not affect portal pressure, which, in contrast, was reduced in livers receiving PG. Finally, all treatments lowered oxidative injury.. Preservation injury in fatty liver is greatly related to nutritional status. Energetic substrate supplementation may represent a clinically feasible protective strategy and a multistep approach adding vasodilators could offer further benefit by acting on different pathogenetic mechanisms.

Topics: Alanine Transaminase; Animal Nutritional Physiological Phenomena; Animals; Dietary Supplements; Fasting; Fatty Liver; Glucose; Glycogen; In Vitro Techniques; Liver; Male; Organ Preservation; Prostaglandins; Rats; Rats, Sprague-Dawley; Reperfusion Injury

Although CCAAT/enhancer-binding protein alpha (C/EBPalpha) is essential for initiating or sustaining several metabolic processes during the perinatal period, the consequences of total ablation of C/EBPalpha during postnatal development have not been investigated. We have created a conditional knock-out model in which the administration of poly(I:C) caused a virtually total deletion of c/ebpalpha (C/EBPalpha(Delta/-) mice) in the liver, spleen, white and brown adipose tissues, pancreas, lung, and kidney of the mice. C/EBPalpha itself was completely ablated in the liver by day 4 after the injection of poly(I:C). There was no noticeable change in phenotype during the first 15 days after the injection. The mice maintained a normal level of fasting blood glucose and responded to the diabetogenic action of streptozotocin. From day 16 onward, the mice developed hypophagia, exhibited severe weight loss, lost triglyceride in white but not brown adipose tissue, became hypoglycemic and hypoinsulinemic, depleted their hepatic glycogen, and developed fatty liver. They also exhibited lowered plasma levels of free fatty acid, triglyceride, and cholesterol, as well as marked changes in hepatic mRNA for C/EBPdelta, peroxisome proliferator-activated receptor alpha, sterol regulatory element-binding protein 1, hydroxymethylglutaryl-coenzyme A reductase, and apolipoproteins. Although basal levels of hepatic mRNA for the cytosolic isoform of phosphoenolpyruvate carboxykinase and glucose-6-phosphatase were reduced, transcription of the genes for these enzymes was inducible by dibutyryl cyclic AMP in C/EBPalpha(Delta/-) mice. The animals died about 1 month after the injection of poly(I:C). These findings demonstrate that C/EBPalpha is essential for the survival of animals during postnatal life and that its ablation leads to distinct biphasic change in metabolic processes.

Topics: Adipose Tissue; Alleles; Animals; Apolipoproteins; Blood Glucose; Blotting, Northern; Blotting, Southern; Blotting, Western; Body Weight; CCAAT-Enhancer-Binding Protein-alpha; CCAAT-Enhancer-Binding Protein-delta; Cholesterol; Crosses, Genetic; Cyclic AMP; Cytosol; Fatty Liver; Gene Deletion; Genotype; Glucokinase; Glucose; Glucose-6-Phosphatase; Glucose-6-Phosphate; Glycogen; Hydroxymethylglutaryl CoA Reductases; Kinetics; Liver; Mice; Mice, Inbred C57BL; Mice, Inbred CBA; Mice, Knockout; Mice, Transgenic; Models, Genetic; Oligonucleotide Array Sequence Analysis; Phosphoenolpyruvate Carboxykinase (ATP); Poly C; Poly I; Polymerase Chain Reaction; PPAR alpha; Protein Isoforms; RNA, Messenger; Streptozocin; Time Factors; Tissue Distribution; Transcription, Genetic; Triglycerides

In the liver, insulin controls both lipid and glucose metabolism through its cell surface receptor and intracellular mediators such as phosphatidylinositol 3-kinase and serine-threonine kinase AKT. The insulin signaling pathway is further modulated by protein tyrosine phosphatase or lipid phosphatase. Here, we investigated the function of phosphatase and tension homologue deleted on chromosome 10 (PTEN), a negative regulator of the phosphatidylinositol 3-kinase/AKT pathway, by targeted deletion of Pten in murine liver. Deletion of Pten in the liver resulted in increased fatty acid synthesis, accompanied by hepatomegaly and fatty liver phenotype. Interestingly, Pten liver-specific deletion causes enhanced liver insulin action with improved systemic glucose tolerance. Thus, deletion of Pten in the liver may provide a valuable model that permits the study of the metabolic actions of insulin signaling in the liver, and PTEN may be a promising target for therapeutic intervention for type 2 diabetes.

Topics: Adipose Tissue; Animals; Blood Glucose; Fasting; Fatty Acids; Fatty Liver; Gene Deletion; Gluconeogenesis; Glucose Tolerance Test; Glycogen; Hepatocytes; Hepatomegaly; Insulin; Insulin Resistance; Liver; Mice; Organ Specificity; RNA, Messenger

Short term high fat feeding in rats results specifically in hepatic fat accumulation and provides a model of non-alcoholic fatty liver disease in which to study the mechanism of hepatic insulin resistance. Short term fat feeding (FF) caused a approximately 3-fold increase in liver triglyceride and total fatty acyl-CoA content without any significant increase in visceral or skeletal muscle fat content. Suppression of endogenous glucose production (EGP) by insulin was diminished in the FF group, despite normal basal EGP and insulin-stimulated peripheral glucose disposal. Hepatic insulin resistance could be attributed to impaired insulin-stimulated IRS-1 and IRS-2 tyrosine phosphorylation. These changes were associated with activation of PKC-epsilon and JNK1. Ultimately, hepatic fat accumulation decreased insulin activation of glycogen synthase and increased gluconeogenesis. Treatment of the FF group with low dose 2,4-dinitrophenol to increase energy expenditure abrogated the development of fatty liver, hepatic insulin resistance, activation of PKC-epsilon and JNK1, and defects in insulin signaling. In conclusion, these data support the hypothesis hepatic steatosis leads to hepatic insulin resistance by stimulating gluconeogenesis and activating PKC-epsilon and JNK1, which may interfere with tyrosine phosphorylation of IRS-1 and IRS-2 and impair the ability of insulin to activate glycogen synthase.

Topics: Animals; Blotting, Western; Cell Membrane; Cytosol; Deoxyglucose; Enzyme Activation; Fatty Acids; Fatty Liver; Glycogen; Glycogen Synthase; Insulin; Insulin Resistance; Lipid Metabolism; Liver; Male; Mitogen-Activated Protein Kinase 8; Mitogen-Activated Protein Kinases; Phosphorylation; Precipitin Tests; Protein Isoforms; Protein Kinase C; Protein Kinase C-epsilon; Protein Transport; Rats; Rats, Sprague-Dawley; RNA, Messenger; Signal Transduction; Time Factors; Tyrosine

The purpose of this study was to investigate the metabolic alterations in the recipient and microcirculatory changes to the graft in the first 3 months after orthotopic liver transplantation (OLT) of nonsteatotic liver grafts from lean rats into obese Zucker rats.. Body weight and plasma lipids were measured for 3 months post-OLT. Graft perfusion (hepatic microcirculatory perfusion [HMP]) and vascular structure were measured in vivo at 3 months. Liver biopsy specimens were obtained throughout for morphologic analysis. Sham-operation obese and lean Zucker rats acted as controls.. Plasma cholesterol levels were elevated from 2 months after OLT, whereas plasma triglyceride levels were reduced (P<0.05). Plasma high-density lipoprotein cholesterol concentrations increased from the first month after OLT (P<0.05). HMP in OLT animals (137+/-3 perfusion units [PU]) (P<0.05) was intermediate between lean (221+/-11 PU) and obese controls (113+/-5 PU). Hepatic cord width in the OLT group was similar to that in lean controls. Mean liver-to-body weight ratios in OLT animals (4.12%+/-0.39%) were significantly higher than in lean controls (3.25%+/-0.1%). The number of viable hepatocytes per high-power field in the OLT animals was lower than in the lean animals but higher than in obese controls (P<0.05). The transplanted livers showed moderate to marked microvesicular fatty change (MIFC) and glycogen deposition at 3 months after OLT.. Transplantation of a nonsteatotic liver into an obese Zucker rat initially has a positive effect on lipid metabolism. However, 3 months after OLT, the donor liver became steatotic with MIFC changes and reduced perfusion. The authors' results emphasize the importance of the recipient's metabolic status in the maintenance of liver graft function after OLT.

Topics: Animals; Biopsy; Body Weight; Cholesterol; Cholesterol, HDL; Fatty Liver; Glycogen; Graft Survival; Liver Circulation; Liver Transplantation; Male; Microcirculation; Obesity; Rats; Rats, Zucker; Triglycerides

The Forkhead box (Fox) transcription factor Foxa2 (HNF-3beta) and related family members Foxa1 (HNF-3alpha) and Foxa3 (HNF-3gamma) act in concert with other hepatocyte nuclear factors (HNF) to coordinately regulate liver-specific gene expression. To circumvent the hepatic functional redundancy of the Foxa proteins, we used the T-77 transgenic (TG) mouse line in which the -3-kb transthyretin (TTR) promoter functioned to increase hepatocyte expression of the Foxa2 cDNA. Adult TG mice exhibited reduced hepatic glycogen and progressive liver injury, but maintained normal serum levels of glucose, insulin, and glucagon. In this study, we further characterized the postnatal liver defect in TTR-FoxA2 TG mice. The postnatal TG mice displayed significant reduction in serum glucose levels and in hepatocyte glycogen storage without increased serum levels of ketone bodies and free fatty acid suggesting that they are not undergoing a starvation response. We show that TG liver developed a substantial transient steatosis, which reached a maximum at postnatal day 5 and is associated with increased expression of hepatic genes involved in fatty acid and triglyceride synthesis, lipid beta-oxidation, and amino acid biosynthesis. Furthermore, transmission electron microscopy analysis of postnatal TG liver revealed extensive mitochondrial membrane damage, which is likely due to reactive oxygen species generated from lipid beta-oxidation. In conclusion, our model proposes that in response to reduction in hepatocyte glycogen storage, the TTR-Foxa2 TG mice survive by maintaining sufficient serum levels of glucose through gluconeogenesis using deaminated amino acids with dicarboxylate products of peroxisomal lipid beta-oxidation shuttled through the tricarboxylic acid cycle.

Topics: Animals; Animals, Newborn; DNA-Binding Proteins; Fatty Acids; Fatty Liver; Gene Expression; Glycogen; Hepatocyte Nuclear Factor 3-beta; Hepatocytes; Intracellular Membranes; Lipid Metabolism; Mice; Mice, Transgenic; Mitochondria, Liver; Nuclear Proteins; Oligonucleotide Array Sequence Analysis; Transcription Factors; Triglycerides

The present study compared the hepatic fatty acid composition of cows that were fed a high energy diet during the dry period to induce fatty liver after parturition with that of control cows. Treated cows had higher concentrations of plasma nonesterified fatty acids as a result of greater lipolysis after parturition than did control cows; consequently, the treated cows accumulated greater amounts of triacylglycerols in the liver. Before parturition, treated cows had lower percentages of oleic acid and higher percentages of linoleic acid than did control cows, but percentages of other fatty acids were similar for both groups. After parturition, percentages of each fatty acid were changed substantially, particularly the four major fatty acids (palmitic, stearic, oleic, and linoleic acids). For treated cows, the percentages of palmitic and oleic acids were higher at 0.5 wk after parturition than at 1 wk before parturition; percentages of stearic and linoleic acids decreased. Unlike treated cows, the percentages of both oleic and linoleic acids in the control cows did not change during that time. Moreover, we found that when lipolysis decreased, as indicated by lower plasma nonesterified fatty acid concentrations, the percentages of each fatty acid gradually rebounded toward the concentrations measured before parturition; this observation indicates that the shift in hepatic fatty acid composition is influenced by lipolysis. The increased lipolysis after parturition led to a vast increase in the hepatic triacyglycerol concentration and to a shift in hepatic fatty acid composition.

Topics: 3-Hydroxybutyric Acid; Animals; Cattle; Cattle Diseases; Energy Intake; Fatty Acids; Fatty Acids, Nonesterified; Fatty Liver; Female; Glycogen; Linoleic Acid; Lipolysis; Liver; Oleic Acid; Palmitic Acid; Pregnancy; Stearic Acids; Triglycerides

Fatty livers are more sensitive to the deleterious effects of ischemia-reperfusion than normal livers. Nutritional status greatly modulates this injury in normal livers, but its role in the specific setting of fatty liver is unknown. This study aimed to determine the effect of nutritional status on warm ischemia-reperfusion injury in rat fatty livers. Fed and fasted rats with normal or fatty liver induced by a choline deficient diet underwent 1 hour of lobar ischemia and reperfusion. Rat survival was determined for 7 days. Serum transaminases, liver histology and cell ultrastructure were assessed before and after ischemia, and at 30 minutes, 2 hours, 8 hours, and 24 hours after reperfusion. Survival was also determined in fatty fasted rats supplemented with glucose before surgery. The preischemic hepatic glycogen was measured in all groups. Whereas survival was similar in fasted and fed rats with normal liver (90% vs. 100%), fasting dramatically reduced survival in rats with fatty liver (14% vs. 64%, P <.01). Accordingly, fasting and fatty degeneration had a synergistic effect in exacerbating liver injury. Mitochondrial damage was a predominant feature of ultrastructural hepatocyte injury in fasted fatty livers. Glucose supplementation partially prevented the fasting-induced depletion of glycogen and improved the 7-day rat survival to 45%. These data indicate that rat fatty livers exposed to normothermic ischemia-reperfusion injury are much more sensitive to fasting than histologically normal livers. Because glucose supplementation improves both the hepatic glycogen stores and the rat survival, a nutritional repletion procedure may be part of a treatment strategy aimed to prevent ischemia-reperfusion injury in fatty livers.

Topics: Alanine Transaminase; Animals; Choline Deficiency; Fatty Liver; Food Deprivation; Glucose; Glycogen; Liver; Male; Microscopy, Electron; Nutritional Status; Rats; Rats, Wistar; Reperfusion Injury; Survival Rate

The purpose of this study was to compare the hepatic enzyme activities of gluconeogenesis between control cows and experimental cows that had been overfed during the dry period to induce fatty liver postpartum. Blood and liver samples were collected 1 wk before and 0.5, 1, 2, and 3 wk after parturition. Before parturition, neither the serum nonesterified fatty acid nor the liver triacylglycerol concentration differed between the two groups. After parturition, these variables were higher in experimental cows than in control cows. Liver glycogen was higher at 1 wk before parturition in experimental cows; sharply decreased after parturition in both groups; and, at 1 wk after parturition, was lower in experimental cows than in control cows. In the liver, activities of phosphoenolpyruvate carboxykinase were significantly lower at 1 wk before and at 0.5 and 2 wk after parturition in experimental cows; in addition, the activities tended to be lower at 1 wk after parturition. Activities of fructose 1,6-bisphosphatase tended to be lower, but activities of glucose 6-phosphatase tended to be higher, at 0.5 wk after parturition in experimental cows than in control cows. Our results suggest that, in fatty infiltrated liver, the rate of gluconeogenesis is not optimal, which results in prolongation of lipolysis, particularly during the first weeks after parturition.

Topics: Animals; Cattle; Cattle Diseases; Energy Intake; Fatty Acids, Nonesterified; Fatty Liver; Female; Fructose-Bisphosphatase; Gluconeogenesis; Glucose-6-Phosphatase; Glycogen; Labor, Obstetric; Liver; Phosphoenolpyruvate Carboxykinase (GTP); Pregnancy; Triglycerides; Weight Gain

Liver steatosis is often attributed to dietary habits. Our previous results have shown that fatty acid synthesis is considerably increased by high carbohydrates-fat free diet (HCFF) given to rats after fasting, and leads to lipid accumulation and morphological alterations in the liver, defined as steatosis. As n-3 polyunsaturated fatty acids are able to counteract lipogenesis induction in vivo and in vitro, we hypothesized that the addition of menhaden oil in a carbohydrate-rich diet might be able to protect the liver against steatosis induced by a fasting-re-feeding transition. Male Wistar rats were first fasted for 48 hr, then re-fed ad lib. for 24 hr with either (1) standard diet; (2) high carbohydrates-fat free diet (HCFF), containing 40% (w/w) starch, 40% saccharose, 16% casein and 4% vitamin mineral mix; or (3) the latter diet containing additionally 5% menhaden oil (HCMO) for 24 hr. Triglyceride (TG) accumulation occurred in liver tissue of rats re-fed with HCFF and HCMO diets after fasting. The addition of menhaden oil led to a strong decrease in serum TG; however, both TG and phospholipid (PL) levels, as well as fatty acid synthase activity, were increased in the liver of HCMO rats as compared with the values obtained in HCFF re-fed rats. Histologically diagnosed steatosis was even more severe when rats received HCMO than HCFF. These results indicate that menhaden oil supplementation does not avoid, but even increases, the degree of steatosis generated in vivo by re-feeding a high carbohydrate diet after fasting.

Topics: Animals; Dietary Carbohydrates; Dietary Supplements; Fasting; Fatty Acid Synthases; Fatty Acids, Nonesterified; Fatty Liver; Fish Oils; Food; Glycogen; Liver; Male; Organ Size; Phospholipids; Rats; Rats, Wistar; Triglycerides

Thirty dairy cows with left abomasal displacement (LAD) and 14 healthy control cows were studied to assess the status of the natural antioxidant vitamin E, lipid peroxidation in the liver (malondialdehyde-formation) and its relationship to hepatic lipidosis. Blood concentrations of alpha-tocopherol, aminotransferase, glutamin dehydrogenase, free fatty acids, beta-hydroxybutyrate and glucose were determined. alpha-tocopherol, tryglyceride, glycogen and malondialdehyde (MDA) in wer liver tissue samples were examined. The dietary alpha-tocopherol intake and its plasma changes in LDA cows were also investigated. Cows were divided into four groups according to their liver triglyceride contents (< 20; 20-80; > 80 mg/g of fresh tissue; and control groups). The lowest plasma vitamin E and the highest liver vitamin E levels were found in cows with highest hepatic triglyceride content. The highest increase in plasma alpha-tocopherol within 5 days was seen in cows with the lowest liver triglyceride (P < 0.01). The liver triglyceride was positively correlated with liver MDA (r = 0.38; P < 0.05) and negatively with plasma alpha-tocopherol (r = -0.41; P < 0.01).

Topics: 3-Hydroxybutyric Acid; Abomasum; Animals; Blood Glucose; Cattle; Cattle Diseases; Fatty Acids, Nonesterified; Fatty Liver; Female; Glutamate Dehydrogenase; Glycogen; Hydroxybutyrates; Lipid Metabolism; Lipid Peroxidation; Liver; Malondialdehyde; Transaminases; Triglycerides; Vitamin E

Keratin 8 (K8)-deficient adult mice develop a severe disease of the gastrointestinal tract characterized mainly by colorectal hyperplasia and inflammation. Given that hepatocytes contain K8/K18 heteropolymers only, this animal model was used to assess the contribution of these simple epithelium keratins to hepatocyte structural and functional integrity. Homozygous mutant (HMZ), heterozygous, and wild-type (WT) mice were examined for hepatocyte structural and metabolic features and their survival to partial hepatectomy. Except for the presence of few necrotic foci, no other tissular or cellular alterations were observed in nonhepatectomized HMZ mouse livers; glycogen and lipid peroxidation levels were essentially normal, but a small reduction in bile flow was observed. In response to a single pentobarbital injection, HMZ mice had longer sleeping times than heterozygous and WT mice. After a two-thirds partial hepatectomy under pentobarbital anesthesia, all HMZ mice died within a few hours, whereas those anesthetized with ether survived for 1 to 2 days. One hour after hepatectomy after pentobarbital anesthesia, many hepatocytes contained erythrocytes and large vacuoles in the cytoplasm, which suggests damage at the plasma membrane level in response to a sudden increase in portal blood flow. In line with these findings, an uptake of trypan blue by HMZ but not WT mouse hepatocytes was observed during a 10 ml/minute perfusion via the portal vein with a dye-supplemented buffer. Subsequent cellular dispersion led to viable WT mouse hepatocytes but largely nonviable HMZ mouse hepatocytes. Better viability was obtained at lower perfusion rates. Partially hepatectomized heterozygous mice developed liver steatosis, a condition that was not associated with a change in K8 content but perhaps linked to the presence of the neo gene. Transgenic HMZ mouse rescue experiments with a full-length K8 gene confirmed that the phenotypic alterations observed in partially hepatectomized HMZ mice were caused by the disruption of the K8 gene. Taken together, these findings demonstrate that simple epithelium keratins are essential for the maintenance of hepatocyte structural and functional integrity.

Topics: Animals; Bile; Blotting, Western; Cell Survival; Epithelium; Fatty Liver; Female; Glycogen; Hepatectomy; Keratins; Lipid Peroxidation; Liver; Liver Regeneration; Male; Mice; Mice, Knockout; Mice, Transgenic; Phenobarbital

We recently reported that fatty liver and hypertriglyceridemia are easily induced by the administration of an inhibitor of fatty acid oxidation (emeriamine; (R)-3-amino-4-trimethylaminobutyric acid) to fasting rats, and that these conditions are not accompanied by the increased de novo synthesis of fatty acid [J. Nutr. Sci. Vitaminol., 42, 111-120, (1996)]. To study whether emeriamine-induced fatty liver is affected by nutrients during recovery from fatty acid oxidation inhibition, we fed rats with either a high-carbohydrate (HCHO) diet or a high-fat (HFAT) diet. Rats fed an HCHO diet following the administration of emeriamine showed a marked decrease in serum and hepatic triglycerides, and a marked increase in hepatic glycogen. The lower levels of serum and hepatic triglycerides were accompanied by decreased activities of the NADPH-generating enzymes such as malic enzyme and glucose-6-phosphate dehydrogenase. By contrast, rats fed an HFAT diet showed less significant changes in hepatic triglyceride and glycogen levels. These results suggest a reciprocal relationship between the triglyceride level and glycogen accumulation caused by HCHO diet during recovery from emeriamine.

Topics: Animals; Betaine; Carnitine; Carnitine Acyltransferases; Cholesterol; Dietary Carbohydrates; Dietary Fats; Enzyme Inhibitors; Fasting; Fatty Acids, Nonesterified; Fatty Liver; Food; Glucosephosphate Dehydrogenase; Glycogen; Liver; Malate Dehydrogenase; Male; Phospholipids; Rats; Rats, Wistar; Triglycerides

We studied development of fatty liver in high producing dairy cows with free access to feed during the dry period and thus showed the combined effects of parturition and prepartum overfeeding. Postpartum liver triacylglycerol concentrations at 1 wk postpartum, as measured in liver biopsies, had increased more than 6-fold, which was preceded or accompanied by an increase in plasma NEFA concentrations. Concentrations of hepatic phospholipid changed only slightly. The amounts of total lipids in serum, very low density lipoproteins, and high density lipoproteins significantly decreased by .5 wk after parturition, and concentrations of high density lipoproteins rose steadily. The pattern was similar for concentrations of total cholesterol and phospholipid in serum. Total lipid concentrations in low density lipoproteins were not altered after parturition. The activity of microsomal phosphatidate phosphohydrolase in the liver showed a transient increase at .5 wk after calving, but activity of microsomal glycerolphosphate acyltransferase remained relatively constant. The activities of diacylglycerol acyltransferase had increased about twice at 1 wk after calving and remained at this high level until at least 4 wk after parturition. The rise in activity of diacyglycerol acyltransferase was probably a response to the extra influx of fatty acids to channel them into triacylglycerol. Activities of microsomal cholinephosphate cytidylyltransferase initially increased after calving and then decreased slightly. Activities of hepatic choline kinase had increased after calving. This study indicates that hepatic triacylglycerol accumulates because of the increased hepatic uptake of NEFA and the simultaneous increase in activity of diacylglycerol acyltransferase.

Topics: Acyltransferases; Animals; Cattle; Cattle Diseases; Choline-Phosphate Cytidylyltransferase; Diacylglycerol O-Acyltransferase; Fatty Acids, Nonesterified; Fatty Liver; Female; Glycerol-3-Phosphate O-Acyltransferase; Glycogen; Lactation; Lipids; Lipoproteins, HDL; Lipoproteins, LDL; Lipoproteins, VLDL; Liver; Nucleotidyltransferases; Phosphatidate Phosphatase; Phospholipids; Postpartum Period; Triglycerides

The aim of the study was to investigate the effect of beta-aescin on the selected indices of sugar and lipid metabolisms in blood and hepatic tissue. The study was performed under the conditions of toxic impairment of the liver caused by carbon tetrachloride or hydrazinsulphate which were used in order to evoke experimentally the steatosis of the liver. The study investigated whether beta-aescin can cause deterioration of hepatic steatosis. Carbon tetrachloride was administered to rats by stomach probe in dosis of 2.5 ml per kg of body weight, or hydrazinsulphate in dosis of 2 mmol per kg of body weight, i.m.. Twenty-four hours after administration of these two substances beta-aescin water solution was administered in dosis of 10 mg per kg of body weight by means of stomach probe. The analysis of blood and liver tissue samples discovered that beta-aescin did not affect the metabolic indices, steatosis of the liver did not become more profound. (Tab. 2, Fig. 11, Ref. 23.)

Topics: Animals; Blood Glucose; Carbon Tetrachloride; Escin; Fatty Liver; Glycogen; Hydrazines; Lipid Metabolism; Male; Rats; Rats, Wistar

Glutamate oxaloacetate transminase (GOT), glutamate dehydrogenase (GDH), sorbitol dehydrogenase (SDH), pseudo-cholinesterase (ChE) and various blood constituents were measured in the plasma of Japanese quail fed 1,1-di(p-chlorophenyl)-2-chloroethylene (DDMU) at low levels for periods ranging from 2 to 32 days. Previous work has shown that DDMU is a potent inducer of hepatic microsomal enzymes causing marked structural changes in the liver. A rapid increase in plasma GOT was observed within 4 days accompanied by an increase in relative liver weight. Plasma GDH and SDH increased to a maximum between 16 and 24 dyas which seems to be associated with hepatic cell proliferation. Plasma ChE showed a steady increase over the time course of DDMU administration. The level of plasma lipid was reduced after 4 days whereas the hepatic lipid content was substantially increased suggesting that the fatty liver condition may be caused by decreased release of triglyceride from the liver. Plasma glucose was reduced at 8 days but there was no evidence of a hyperglycaemic state. The changes noted after 2 days of DDMU diet were confirmed by measurements on birds 18 h after oral dosing the DDMU. The study demonstrates the value of plasma enzyme measurements for the early detection of toxic effects and indicates that DDMU administration leads to extrahepatic effects in addition to those previously described in the liver.

Topics: Animals; Aspartate Aminotransferases; Blood Glucose; Butyrylcholinesterase; Coturnix; DDT; Dichlorodiphenyl Dichloroethylene; Enzyme Induction; Enzymes; Fatty Liver; Female; Glutamate Dehydrogenase; Glycogen; L-Iditol 2-Dehydrogenase; Lipids; Liver

Topics: Animals; Diabetes Mellitus; Diabetes Mellitus, Experimental; Dogs; Fatty Liver; Female; Glycogen; Humans; Hyperglycemia; Insulin; Insulin Secretion; Islets of Langerhans; Lipid Metabolism; Liver; Liver Cirrhosis; Liver Diseases; Male; Rabbits; Rats

The hepatic lesion in Reye's syndrome (acute encephalopathy with fatty degeneration of viscera) was studied by light microscopy of sequential biopsy specimens obtained in 49 children. The hepatic lesion is a morphologically characteristic, rapidly evolving, and reversible toxic hepatitis. In specimens obtained with 48 hr of onset of neurological deterioration, the severity of the diffuse microvesicular steatosis is best appreciated in frozen sections stained for lipid content. Variation in severity of hepatocyte glycogen depletion in early biopsies correlates with other histological measures of severity, and with the occurrence of hypoglycemia, severity of the encephalopathy at the time of admission, and mortality rate. Histochemical studies suggest that the hepatic lesion is attributable to mitochondrial injury and other evidence that supports this hypothesis is briefly reviewed. The etiology of the syndrome and its relationship to the viral disease which usually precedes it are unknown.

Topics: Brain Diseases; Chemical and Drug Induced Liver Injury; Fatty Liver; Glycogen; Humans; Lipid Metabolism; Liver; Mitochondria, Liver; Reye Syndrome

Topics: Aflatoxins; Animals; Blood Glucose; Brain Diseases; Drug Synergism; Enterovirus Infections; Fatty Acids, Unsaturated; Fatty Liver; Glycogen; Hexachlorocyclohexane; Hypoglycemia; Liver; Mengovirus; Mice; Microscopy, Electron; Mitochondria, Liver; Polychlorinated Biphenyls; Rats; Reye Syndrome; Syndrome; Toxins, Biological; Triglycerides; Valerates

Topics: Aged; Carbohydrate Metabolism; Child; Diabetes Complications; Drug-Related Side Effects and Adverse Reactions; Fatty Liver; Female; Glycogen; Humans; Lipid Metabolism; Liver Diseases; Male; Metabolic Diseases; Oxygen Consumption; Proteins

Topics: Alanine Transaminase; Animals; Aspartate Aminotransferases; Cold Temperature; Creatine; Fatty Liver; Fructose-Bisphosphate Aldolase; Glycogen; Hair; Hematocrit; Hemorrhage; Hypothermia; Isoenzymes; Kidney; L-Lactate Dehydrogenase; Leukocyte Count; Lipids; Liver; Liver Glycogen; Lung Diseases; Male; Muscles; Myocardium; Necrosis; Phosphotransferases; Rabbits; Time Factors

Topics: Animals; Blood Glucose; Brain Diseases; Fatty Liver; Glucagon; Gluconeogenesis; Glucose; Glycogen; Growth Hormone; Haplorhini; Humans; Hypoglycemia; Insulin; Liver; Mice; Pyruvates; Rats; Reye Syndrome

Topics: Age Factors; Animals; Biopsy; Endoplasmic Reticulum; Fatty Liver; Fructose; Glycogen; Haplorhini; Kwashiorkor; Liver; Microscopy, Electron; Papio; Protein-Energy Malnutrition; Sucrose; Triglycerides

Topics: Animals; Anura; Endoplasmic Reticulum; Fasting; Fatty Liver; Glycogen; Inclusion Bodies; Lipids; Liver; Lysosomes; Microscopy, Electron; Mitochondria; Necrosis; Seasons; Starvation

Topics: Animals; Arteries; Arteriosclerosis; Blood Glucose; Cholesterol; Diet, Atherogenic; Fatty Acids, Nonesterified; Fatty Liver; Glycogen; Hyperlipidemias; Intestinal Absorption; Lipoproteins; Liver; Male; Metformin; Phenformin; Phospholipids; Rabbits

Topics: Animals; Carbon Tetrachloride; Cold Temperature; Ethanol; Fatty Liver; Glycogen; Lipid Metabolism; Lipid Mobilization; Norepinephrine; Prostaglandins; Rats

Topics: Administration, Oral; Adult; Aged; Alanine Transaminase; Aspartate Aminotransferases; Blood Glucose; Clofibrate; Fatty Liver; Glycogen; Humans; Hyperlipidemias; Lipids; Liver; Long-Term Care; Middle Aged; Triglycerides

Topics: Animals; Choline; Endoplasmic Reticulum; Ethanol; Fatty Liver; Glycogen; Golgi Apparatus; Lipids; Liver; Lysosomes; Male; Microscopy, Electron; Mitochondria, Liver; Mixed Function Oxygenases; Phosphatidylcholines; Phospholipids; Rats; Rats, Inbred Strains; Triglycerides

Topics: Animals; Carbon Tetrachloride; Carbon Tetrachloride Poisoning; Choline; Choline Deficiency; Dietary Fats; Dietary Proteins; Fatty Liver; Female; Glycogen; Histocytochemistry; Injections, Subcutaneous; Mice

Topics: Aging; Animals; Bile; Carbon Tetrachloride; DNA; Fatty Liver; Glycogen; Lipid Metabolism; Liver; Liver Cirrhosis, Experimental; Liver Regeneration; Methods; Rats; RNA

Topics: Acid Phosphatase; Alkaline Phosphatase; Animals; Choline Deficiency; Electron Transport Complex IV; Esterases; Fats; Fatty Acids; Fatty Liver; Glycogen; Histocytochemistry; Liver; Phospholipids; Protein Deficiency; Rats; Succinate Dehydrogenase; Time Factors

Topics: Animals; Cholesterol; Dental Pulp; Dental Pulp Diseases; Fatty Liver; Fluorides; Glycogen; Lipids; Liver; Phospholipids; Proteins; Rats

Topics: Animals; Fatty Liver; Glycogen; Hepatectomy; Histocytochemistry; Lipid Metabolism; Liver; Male; Microscopy, Electron; Rats

Topics: Adrenal Glands; Animals; Blood Vessels; Carbohydrate Metabolism; Clostridium perfringens; Fats; Fatty Liver; Glycogen; Guinea Pigs; Heart; Histocytochemistry; Injections, Intramuscular; Kidney; Liver; Lung; Lymph Nodes; Methods; Myocardium; Phospholipases; Proteins; Spleen

Topics: Animals; Fatty Liver; Glycogen; Humans; Liver Diseases; Liver Glycogen; Rabbits

Topics: Animals; Diet; Fatty Liver; Glycogen; Glycogenolysis; Lipotropic Agents; Liver Glycogen; Rats; Thyroxine

Topics: Fatty Liver; Glycogen; Humans; Keto Acids; Ketones; Lactates; Liver Diseases; Pyruvates

Topics: Adipose Tissue; Animals; Carbon Tetrachloride; Fatty Liver; Glycogen; Guinea Pigs; Kidney; Muscles; Rats; Thyroidectomy; Water