glycogen and Non-alcoholic-Fatty-Liver-Disease

The incidence of obesity, insulin resistance, and type II diabetes (T2DM) continues to rise worldwide. The liver is a central insulin-responsive metabolic organ that governs whole-body metabolic homeostasis. Therefore, defining the mechanisms underlying insulin action in the liver is essential to our understanding of the pathogenesis of insulin resistance. During periods of fasting, the liver catabolizes fatty acids and stored glycogen to meet the metabolic demands of the body. In postprandial conditions, insulin signals to the liver to store excess nutrients into triglycerides, cholesterol, and glycogen. In insulin-resistant states, such as T2DM, hepatic insulin signaling continues to promote lipid synthesis but fails to suppress glucose production, leading to hypertriglyceridemia and hyperglycemia. Insulin resistance is associated with the development of metabolic disorders such as cardiovascular and kidney disease, atherosclerosis, stroke, and cancer. Of note, nonalcoholic fatty liver disease (NAFLD), a spectrum of diseases encompassing fatty liver, inflammation, fibrosis, and cirrhosis, is linked to abnormalities in insulin-mediated lipid metabolism. Therefore, understanding the role of insulin signaling under normal and pathologic states may provide insights into preventative and therapeutic opportunities for the treatment of metabolic diseases. Here, we provide a review of the field of hepatic insulin signaling and lipid regulation, including providing historical context, detailed molecular mechanisms, and address gaps in our understanding of hepatic lipid regulation and the derangements under insulin-resistant conditions. © 2023 American Physiological Society. Compr Physiol 13:4785-4809, 2023.

Topics: Diabetes Mellitus, Type 2; Glycogen; Homeostasis; Humans; Insulin; Insulin Resistance; Lipid Metabolism; Liver; Non-alcoholic Fatty Liver Disease; Triglycerides

Non-alcoholic fatty liver disease (NAFLD) has emerged as the most prevalent liver disease in industrialized countries. It is regarded as the hepatic manifestation of the metabolic syndrome (MetS) resulting from insulin resistance. Moreover, insulin resistance impairs glycogen synthesis, postprandially diverting a substantial amount of carbohydrates to the liver and storing them there as fat. NAFLD has far-reaching metabolic consequences involving glucose and lipoprotein metabolism disorders and risk of cardiovascular disease, the leading cause of death worldwide. No pharmaceutical options are currently approved for the treatment of NAFLD. Exercise training and dietary interventions remain the cornerstone of NAFLD treatment. Current international guidelines state that the primary goal of nutritional therapy is to reduce energy intake to achieve a 7%-10% reduction in body weight. Meal replacement therapy (formula diets) results in more pronounced weight loss compared to conventional calorie-restricted diets. However, studies have shown that body mass index (BMI) or weight reduction is not obligatory for decreasing hepatic fat content or to restore normal liver function. Recent studies have achieved significant reductions in liver fat with eucaloric diets and without weight loss through macronutrient modifications. Based on this evidence, an integrative nutritional therapeutic concept was formulated that combines the most effective nutrition approaches termed "liver-fasting." It involves the temporary use of a low calorie diet (total meal replacement with a specific high-protein, high-soluble fiber, lower-carbohydrate formula), followed by stepwise food reintroduction that implements a Mediterranean style low-carb diet as basic nutrition.

Topics: Caloric Restriction; Diet, Carbohydrate-Restricted; Diet, Mediterranean; Exercise; Glycogen; Heart Disease Risk Factors; Humans; Insulin Resistance; Lipid Metabolism; Liver; Non-alcoholic Fatty Liver Disease; Nutrition Therapy; Nutritional Physiological Phenomena; Weight Loss

Succinate and succinate receptor 1 (SUCNR1) are linked to fibrotic remodeling in models of non-alcoholic fatty liver disease (NAFLD), but whether they have roles beyond the activation of hepatic stellate cells remains unexplored. We investigated the succinate/SUCNR1 axis in the context of NAFLD specifically in hepatocytes.. We studied the phenotype of wild-type and Sucnr1. Sucnr1 was upregulated in murine liver and primary hepatocytes in response to diet-induced NASH. Sucnr1 deficiency provoked both beneficial (reduced fibrosis and endoplasmic reticulum stress) and detrimental (exacerbated steatosis and inflammation and reduced glycogen content) effects in the liver, and disrupted glucose homeostasis. Studies in vitro revealed that hepatocyte injury increased Sucnr1 expression, which when activated improved lipid and glycogen homeostasis in damaged hepatocytes. In humans, SUCNR1 expression was a good determinant of NAFLD progression to advanced stages. In a population at risk of NAFLD, circulating succinate was elevated in patients with a fatty liver index (FLI) ≥60. Indeed, succinate had good predictive value for steatosis diagnosed by FLI, and improved the prediction of moderate/severe steatosis through biopsy when added to an FLI algorithm.. We identify hepatocytes as target cells of extracellular succinate during NAFLD progression and uncover a hitherto unknown function for SUCNR1 as a regulator of hepatocyte glucose and lipid metabolism. Our clinical data highlight the potential of succinate and hepatic SUCNR1 expression as markers to diagnose fatty liver and NASH, respectively.

Topics: Animals; Disease Models, Animal; Fibrosis; Glucose; Glycogen; Hepatocytes; Humans; Liver; Mice; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease; Succinates

Topics: Animals; Diet, High-Fat; Glycogen; Liver; Mice; Nanoparticles; Non-alcoholic Fatty Liver Disease; Oxidative Stress; Resveratrol

Non-alcoholic steatohepatitis (NASH) is a chronic disease characterized by inflammation, steatosis, and liver fibrosis. The liver is particularly affected by alterations in lipid metabolism. Our aim was to evaluate the effect of β-hydroxyphosphocarnitine (β-HPC) on NASH induced in rats.. NASH was characterized by elevated triglycerides, elevated liver damage enzymes, and the presence of necrosis, inflammation, steatosis, and fibrosis. Significant amounts of glycogen were found, along with α-SMA positive cells in fibrosis areas. The over-expression of SREBP-1 in cytoplasm and nuclei was evident. Animals with NASH treated with β-HPC showed a significant reduction in inflammation, necrosis, and glycogen content in the liver. A reduction in α-SMA and SREBP-1 immunopositive cells correlated with a significant reduction in the degree of fibrosis and steatosis found in liver tissue. β-HPC reduced the levels of ALP and GGT, and significantly reduced triglyceride levels. Animals treated with β-HPC did not show any alterations in liver enzyme function.. Our research shows that β-HPC can improve liver function and morphology in the case of NASH induced in rats, suggesting β-HPC could be potentially used in the treatment of NASH.

Topics: Animals; Carnitine; Cholesterol; Diet, High-Fat; Disease Models, Animal; Fructose; Glucose; Glycogen; Inflammation; Liver; Liver Cirrhosis; Necrosis; Non-alcoholic Fatty Liver Disease; Organophosphates; Rats; Rats, Wistar; Sterol Regulatory Element Binding Protein 1; Triglycerides

Pandemic vitamin D deficiency is associated with insulin resistance and type 2 diabetes. Vitamin D supplementation has been reported to have improved glucose homeostasis. However, its mechanism to improve insulin sensitivity remains unclear.. Male C57BL/6J mice are fed with/without vitamin D control (CD) or Western (WD) diets for 15 weeks. The vitamin-D-deficient lean (CDVDD) and obese (WDVDD) mice are further subdivided into two groups. One group is re-supplemented with vitamin D for 6 weeks and hepatic insulin signaling is examined. Both CD and WD mice with vitamin D deficiency developed insulin resistance. Vitamin D supplementation in CDVDD mice significantly improved insulin sensitivity, hepatic inflammation, and antioxidative capacity. The hepatic insulin signals like pAKT, pFOXO1, and pGSK3β are increased and the downstream Pepck, G6pase, and Pgc1α are reduced. Furthermore, the lipogenic genes Srebp1c, Acc, and Fasn are decreased, indicating that hepatic lipid accumulation is inhibited.. The results demonstrate that vitamin D deficiency induces insulin resistance. Its supplementation has significant beneficial effects on pathophysiological mechanisms in type 2 diabetes but only in lean and not in the obese phenotype. The increased subacute inflammation and insulin resistance in obesity cannot be significantly alleviated by vitamin D supplementation. This needs to be taken into consideration in the design of new clinical trials.

Topics: Animals; Body Weight; Diet, High-Fat; Forkhead Box Protein O1; Gluconeogenesis; Glucose; Glycogen; Hepatitis; Insulin Resistance; Liver; Male; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease; Obesity; Oxidative Stress; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Vitamin D; Vitamin D Deficiency

We investigated the role of secondhand smoke (SHS) exposure, independently of diet, in the development of chronic liver disease. Standard diet-fed mice were exposed to SHS (5 h/day, 5 days/week for 4 months). Genome-wide gene expression analysis, together with molecular pathways and gene network analyses, and histological examination for lipid accumulation, inflammation, fibrosis, and glycogen deposition were performed on the liver of SHS-exposed mice and controls, upon termination of exposure and after one-month recovery in clean air. Aberrantly expressed transcripts were found in the liver of SHS-exposed mice both pre- and post-recovery in clean air (

Topics: Animals; Apoptosis; Cluster Analysis; Collagen; Endoplasmic Reticulum; Glycogen; Lipid Metabolism; Liver; Male; Mice; Mice, Inbred C57BL; Necrosis; Non-alcoholic Fatty Liver Disease; Phenotype; Principal Component Analysis; Tobacco Smoke Pollution; Transcriptome

Glycogen storage disease (GSD) type 1a is an inborn error of metabolism caused by defective glucose-6-phosphatase catalytic subunit (G6PC) activity. Patients with GSD 1a exhibit severe hepatomegaly due to glycogen and triglyceride (TG) accumulation in the liver. We have shown that the activity of carbohydrate response element binding protein (ChREBP), a key regulator of glycolysis and de novo lipogenesis, is increased in GSD 1a. In the current study, we assessed the contribution of ChREBP to nonalcoholic fatty liver disease (NAFLD) development in a mouse model for hepatic GSD 1a.. Liver-specific G6pc-knockout (L-G6pc. Attenuation of hepatic ChREBP induction in GSD 1a liver aggravates hepatomegaly because of further accumulation of glycogen and lipids as a result of reduced glycolysis and suppressed VLDL-TG secretion. TM6SF2, critical for VLDL formation, was identified as a ChREBP target in mouse liver. Altogether, our data show that enhanced ChREBP activity limits NAFLD development in GSD 1a by balancing hepatic TG production and secretion.

Topics: Adipose Tissue, White; Animals; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; Dependovirus; Disease Models, Animal; Gene Knockdown Techniques; Genetic Vectors; Glucose-6-Phosphatase; Glycogen; Glycogen Storage Disease Type I; Glycolysis; Hepatocytes; Humans; Lipogenesis; Lipoproteins, VLDL; Liver; Male; Mice; Mice, Knockout; Non-alcoholic Fatty Liver Disease; RNA, Small Interfering; Triglycerides

Insulin resistance (IR) contributes to diabetes and aging. Ultraconserved elements (UCEs) are a class of long noncoding RNAs (lncRNAs) that are 100% conserved in humans, mice, and rats. We identified the lncRNA uc.333 using an lncRNA microarray and then used quantitative real-time polymerase chain reaction to analyze its expression in the livers of nonalcoholic fatty liver disease (NAFLD) patients, db/db mice, high-fat diet-fed mice, IL-6-treated mice, and TNF-α-treated mice. The underlying mechanisms of uc.333 in IR were investigated using fluorescence in situ hybridization, Western blot, and miRNA microarray analyses. The results revealed that uc.333 expression was decreased in liver tissues from NAFLD patients and treated mice. Furthermore, overexpression of uc.333 decreased IR, whereas knocking down uc.333 increased IR. We also confirmed that uc.333 binds to miR-223 and that the levels of miR-223 were increased in the livers of patients and treated mice. These findings showed that uc.333 improves IR by binding to miR-223; thus, uc.333 may be a useful target for the treatment and prevention of IR.

Topics: Adipose Tissue; Animals; Base Sequence; Conserved Sequence; Dietary Fats; Forkhead Box Protein O1; Glucose; Glycogen; Hep G2 Cells; Hepatocytes; Humans; Insulin Resistance; Interleukin-6; Liver; Male; Mice; MicroRNAs; Non-alcoholic Fatty Liver Disease; Oligonucleotide Array Sequence Analysis; Phosphorylation; Proto-Oncogene Proteins c-akt; RNA, Long Noncoding; RNA, Small Interfering; Tumor Necrosis Factor-alpha

Non-alcoholic fatty liver disease and steatohepatitis are highly associated with obesity and type 2 diabetes mellitus. Cotadutide, a GLP-1R/GcgR agonist, was shown to reduce blood glycemia, body weight and hepatic steatosis in patients with T2DM. Here, we demonstrate that the effects of Cotadutide to reduce body weight, food intake and improve glucose control are predominantly mediated through the GLP-1 signaling, while, its action on the liver to reduce lipid content, drive glycogen flux and improve mitochondrial turnover and function are directly mediated through Gcg signaling. This was confirmed by the identification of phosphorylation sites on key lipogenic and glucose metabolism enzymes in liver of mice treated with Cotadutide. Complementary metabolomic and transcriptomic analyses implicated lipogenic, fibrotic and inflammatory pathways, which are consistent with a unique therapeutic contribution of GcgR agonism by Cotadutide

Topics: Animals; Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Glucagon-Like Peptide-1 Receptor; Glycogen; Lipogenesis; Liver; Liver Cirrhosis; Male; Mice; Mice, Knockout; Mitochondria; Non-alcoholic Fatty Liver Disease; Peptides; Proteomics

The ribotoxin deoxynivalenol (DON) is a trichothecene found on cereals responsible for mycotoxicosis in both humans and farm animals. DON toxicity is characterized by reduced food intake, diminished nutritional efficiency and immunologic effects. The present study was designed to further characterize the alterations in energy metabolism induced by DON intoxication. We demonstrated that acute DON intoxication triggered liver steatosis associated with an altered expression of genes related to lipids oxidation, lipogenesis and lipolysis. This steatosis was concomitant to anorexia, hypoglycemia and a paradoxical transient insulin release. DON treatment resulted also in stimulation of central autonomic network regulating sympathetic outflow and adrenaline and glucocorticoids secretion. Furthermore, an increased expression of genes linked to inflammation and reticulum endoplasmic stress was observed in the liver of DON-treated mice. Finally, we propose that lipids mobilization from adipose tissues (AT) induced by DON intoxication drives hepatic steatosis since (1) genes encoding lipolytic enzymes were up-regulated in AT and (2) plasma concentration of triglycerides (TGs) and non-esterified fatty acids were increased during DON intoxication. Altogether, these data demonstrate that DON induced hormonal and metabolic dysregulations associated with a spectrum of hepatic abnormalities, evocative of a non-alcoholic fatty liver disease.

Topics: Animal Feed; Animals; Biomarkers; Cytokines; Disease Models, Animal; Endoplasmic Reticulum Stress; Energy Metabolism; Fatty Acids; Food Contamination; Glycogen; Hormones; Immunohistochemistry; Inflammation Mediators; Lipid Metabolism; Lipolysis; Liver; Male; Mice; Non-alcoholic Fatty Liver Disease; Oxidation-Reduction; Trichothecenes

Non-alcoholic fatty liver disease (NAFLD) is a chronic liver disease. The literature suggests that the aryl hydrocarbon receptor (AHR) may be a key player in the pathogenesis of NAFLD, and it can modulate the synthesis of cytochrome P450 1A1 (CYP1A1) and tumor necrosis factor-α (TNF-α). Previous studies have shown that CYP1A1 is a key enzyme of oxidative stress, TNF-α is involved in the formation of insulin resistance (IR), oxidative stress and insulin resistance are the key factors for the formation of NAFLD. Therefore, it can be said that AHR may participate in contributing to NAFLD by regulating CYP1A1 and TNF-α. Alpha-naphthoflavone (ANF) is an effective AHR inhibitor. The present study was designed to explore the hepatoprotective effect of ANF in high fat diet (HFD)-induced NAFLD mice and oleic acid (OA)-treated HepG2 hepatocytes. Mice were fed HFD to induce NAFLD, HepG2 cells were exposed to OA to induce hepatocyte injury, and ANF significantly reduced mouse and cellular liver damage compared to the HFD-induced NAFLD and OA-treated HepG2 hepatocytes. ANF treatment reduces liver damage by reducing ROS and IR, the data show that ANF inhibits the expression of AHR, CYP1A1 and TNF-α in NAFLD. Taken together, these findings show that ANF alleviate NAFLD via regulation of AHR/CYP1A1 and AHR/TNF-α pathways, which may have potential for further development as novel therapeutic agents for NAFLD.

Topics: Animals; Benzoflavones; Catalase; Cell Proliferation; Diet, High-Fat; Glycogen; Hep G2 Cells; Hepatocytes; Humans; Insulin Resistance; Lipid Droplets; Lipid Metabolism; Liver; Male; Malondialdehyde; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease; Oleic Acid; Oxidative Stress; Superoxide Dismutase

Non-alcoholic fatty liver disease (NAFLD) is currently evolving as the most common liver disease worldwide. Dyslipidemia, pathoglycemia and insulin resistance are the major risk factors for the development of NAFLD. To date, no effective drug therapies for this condition have been approved.. The present study was to investigate the protective effects of yangonin, a kavalactone isolated from Kava, against NAFLD and further elucidate the mechanisms in vivo and in vitro.. A high-fat diet (HFD) induced mouse NAFLD model was used with or without yangonin treatment.. The body weight, relative liver weight and serum biochemical indicators were measured. H&E and Oil Red O staining were used to identify the amelioration of the liver histopathological changes. Serum and hepatic triglyceride, free fatty acids and total cholesterol were analyzed. siRNA, quantitative real-time PCR and Western blot assay were used to clarify the mechanisms underlying yangonin protection.. Yangonin had obvious protective effects against NAFLD via farnesoid X receptor (FXR) activation. Through FXR activation, yangonin attenuated lipid accumulation in the liver via inhibition of hepatic lipogenesis-related protein including sterol regulatory element-binding protein 1c (SREBP-1c), fatty acid synthetase (FAS), acetyl-CoA carboxylase 1 (ACC1) and stearoyl-CoA desaturase 1 (SCD1). Besides, yangonin promoted lipid metabolism through an induction in genes required for lipoprotein lipolysis and fatty acid β-oxidation. Furthermore, yangonin modulated blood glucose homeostasis through regulation of gluconeogenesis-related gene phosphoenol pyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase), and glycogen synthesis-related gene glycogen synthase kinase 3β (GSK3β) and pyruvate dehydrogenase (PDase). Also, yangonin increased insulin sensitivity through upregulating phosphorylation of insulin responsive substrate 1, 2 (IRS-1 and IRS-2). Then, in vivo and in vitro evidence further demonstrated the involvement of FXR activation in yangonin hepatoprotection.. Yangonin protects against NAFLD due to its activation of FXR signalling to inhibit hepatic lipogenesis and gluconeogenesis, and to promote lipid metabolism and glycogen synthesis, as well as insulin sensitivity.

Topics: Animals; Diet, High-Fat; Gluconeogenesis; Glucose; Glycogen; Insulin; Insulin Resistance; Lipid Metabolism; Lipogenesis; Liver; Male; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease; Protective Agents; Pyrones; Receptors, Cytoplasmic and Nuclear; Triglycerides

Type 2 diabetes mellitus contributes to an increased risk of metabolic and morphological changes in key organs, such as the liver. We aimed to assess the effect of the açaí seed extract (ASE) associated with exercise training on hepatic steatosis induced by high-fat (HF) diet plus streptozotocin (STZ) in rats. Type 2 diabetes was induced by feeding rats with HF diet (55% fat) for 5 weeks, followed by a single low dose of STZ (35 mg/kg i.p.). Control and diabetic groups were subdivided into four groups that were fed with standard chow diet for 4 weeks. Control (C) group was subdivided into Sedentary C, Training C, ASE Sedentary C and ASE Training C. Diabetic (D) group was subdivided into Sedentary D, Training D, ASE Sedentary D and ASE Training D. ASE (200 mg/kg/day) was administered by intragastric gavage, and the exercise training was performed on a treadmill (30 min/day; 5 days/week). Treatment with ASE associated with exercise training reduced the blood glucose (70.2%), total cholesterol (81.2%), aspartate aminotransferase (51.7%) and hepatic triglyceride levels (66.8%) and steatosis (72%) in ASE Training D group compared with the Sedentary D group. ASE associated with exercise training reduced the hepatic lipogenic proteins' expression (77.3%) and increased the antioxidant defense (63.1%), pAMPK expression (70.2%), cholesterol transporters (71.1%) and the pLKB1/LKB1 ratio (57.1%) in type 2 diabetic rats. In conclusion, ASE treatment associated with exercise training protects against hepatic steatosis in diabetic rats by reducing hepatic lipogenesis and increasing antioxidant defense and cholesterol excretion.

Topics: Animals; Antioxidants; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Enzymes; Euterpe; Glycogen; Lipid Metabolism; Liver; Male; Non-alcoholic Fatty Liver Disease; Physical Conditioning, Animal; Plant Extracts; Protein Carbonylation; Proteins; Rats, Wistar; Seeds

Topics: AMP-Activated Protein Kinase Kinases; AMP-Activated Protein Kinases; Animals; Biomarkers; Blood Glucose; Disease Models, Animal; Enzyme Activation; Fructose; Glucosides; Glycogen; Insulin; Insulin Resistance; Lipids; Lipogenesis; Liver; Male; Monoterpenes; Non-alcoholic Fatty Liver Disease; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins c-akt; Rats, Sprague-Dawley; Signal Transduction

Non-alcoholic fatty liver disease (NAFLD) has become a predictive factor of death from many diseases. The purpose of the present study is to investigate the protective effect of glycyrrhizic acid (GA), a natural triterpene glycoside, on NAFLD induced by a high-fat diet (HFD) in mice, and further to elucidate the mechanisms underlying GA protection. GA treatment significantly reduced the relative liver weight, serum ALT, AST activities, levels of serum lipid, blood glucose and insulin. GA suppressed lipid accumulation in liver. Further mechanism investigation indicated that GA reduced hepatic lipogenesis via downregulating SREBP-1c, FAS and SCD1 expression, increased fatty acids β-oxidation via an increase in PPARα, CPT1α and ACADS, and promoted triglyceride metabolism through inducing LPL activity. Furthermore, GA reduced gluconeogenesis through repressing PEPCK and G6Pase, and increased glycogen synthesis through an induction in gene expression of PDase and GSK3β. In addition, GA increased insulin sensitivity through upregulating phosphorylation of IRS-1 and IRS-2. In conclusion, GA produces protective effect against NAFLD, due to regulation of genes involved in lipid, glucose homeostasis and insulin sensitivity.

Topics: Animals; Body Weight; Cytoprotection; Diet, High-Fat; Fatty Acids; Gene Expression Regulation; Gluconeogenesis; Glucose Tolerance Test; Glycogen; Glycyrrhizic Acid; Insulin Resistance; Liver; Male; Mice; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease; Organ Size; Receptors, Cytoplasmic and Nuclear; Triglycerides

Glucocorticoids have been implicated in nonalcoholic fatty liver diseases (NAFLD). The influence of a palatable diet on the response to stress is controversial. This study explored whether a high-sucrose diet could protect from hepatic steatosis induced by chronic restraint stress in young adult rats. Male Wistar rats aged 21 days were allocated into four groups (n = 6-8 per group): control, chronic restraint stress, 30% sucrose diet, and 30% sucrose diet plus chronic restraint stress. After being exposed to either tap water or sucrose solution during eight weeks, half of the rats belonging to each group were subject or not to repeated restraint stress (1 h per day, 5 days per week) during four weeks. Triacylglycerol (TAG), oxidative stress, activity of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD-1), infiltration of immune cells, and glycogen amount in the liver were quantified. Serum concentrations of corticosterone and testosterone were also measured. The stressed group showed normal serum concentrations of corticosterone and did not have hepatic steatosis. However, this group showed increased glycogen, inflammation, mild fibrosis, oxidative stress, and a high activity of 11β-HSD-1 in the liver. The group exposed to the high-sucrose diet had lower concentrations of corticosterone, hepatic steatosis and moderate fibrosis. The group subject to high-sucrose diet plus chronic restraint stress showed low concentrations of corticosterone, hepatic steatosis, oxidative stress, and high concentrations of testosterone. Thus, restraint stress and a high-sucrose diet each generate different components of nonalcoholic fatty liver in young adult rats. The combination of both the factors could promote a faster development of NAFLD.

Topics: 11-beta-Hydroxysteroid Dehydrogenase Type 1; Animals; Chronic Disease; Corticosterone; Diet; Dietary Sucrose; Glycogen; Inflammation; Liver; Liver Cirrhosis; Male; Non-alcoholic Fatty Liver Disease; Oxidative Stress; Rats; Rats, Wistar; Restraint, Physical; Stress, Psychological; Sweetening Agents; Testosterone; Triglycerides

Among the 22 fibroblast growth factors (FGFs), FGF21 has now emerged as a key metabolic regulator. However, the mechanism whereby FGF21 mediates its metabolic actions per se remains largely unknown. Here, we show that FGF21 represses mammalian target of rapamycin complex 1 (mTORC1) and improves insulin sensitivity and glycogen storage in a hepatocyte-autonomous manner. Administration of FGF21 in mice inhibits mTORC1 in the liver, whereas FGF21-deficient mice display pronounced insulin-stimulated mTORC1 activation and exacerbated hepatic insulin resistance (IR). FGF21 inhibits insulin- or nutrient-stimulated activation of mTORC1 to enhance phosphorylation of Akt in HepG2 cells at both normal and IR condition. TSC1 deficiency abrogates FGF21-mediated inhibition of mTORC1 and augmentation of insulin signaling and glycogen synthesis. Strikingly, hepatic βKlotho knockdown or hepatic hyperactivation of mTORC1/ribosomal protein S6 kinase 1 abrogates hepatic insulin-sensitizing and glycemic-control effects of FGF21 in diet-induced insulin-resistant mice. Moreover, FGF21 improves methionine- and choline-deficient diet-induced steatohepatitis.. FGF21 acts as an inhibitor of mTORC1 to control hepatic insulin action and maintain glucose homeostasis, and mTORC1 inhibition by FGF21 has the therapeutic potential for treating IR and type 2 diabetes. (Hepatology 2016;64:425-438).

Topics: Animals; Diet, High-Fat; Fibroblast Growth Factors; Glycogen; Insulin; Insulin Resistance; Klotho Proteins; Liver; Male; Mechanistic Target of Rapamycin Complex 1; Membrane Proteins; Mice, Inbred C57BL; Mice, Knockout; Multiprotein Complexes; Non-alcoholic Fatty Liver Disease; Sucrose; TOR Serine-Threonine Kinases

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

We have previously shown that in response to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-elicited NAFLD progression, central carbon, glutaminolysis, and serine/folate metabolism are reprogrammed to support NADPH production and ROS defenses. To further investigate underlying dose-dependent responses associated with TCDD-induced fibrosis, female C57BL/6 mice were gavaged with TCDD every 4 days (d) for 28 d or 92 d. RNA-Seq, ChIP-Seq (2 h), and 28 d metabolomic (urine, serum, and hepatic extract) analyses were conducted with complementary serum marker assessments at 92 d. Additional vehicle and 30 µg/kg treatment groups were allowed to recover for 36 d following the 92-d treatment regimen to examine recovery from TCDD-elicited fibrosis. Histopathology revealed dose-dependent increases in hepatic fat accumulation, inflammation, and periportal collagen deposition at 92 days, with increased fibrotic severity in the recovery group. Serum proinflammatory and profibrotic interleukins-1β, -2, -4, -6, and -10, as well as TNF-α and IFN-γ, exhibited dose-dependent induction. An increase in glucose tolerance was observed with a concomitant 3.0-fold decrease in hepatic glycogen linked to increased ascorbic acid biosynthesis and proline metabolism, consistent with increased fibrosis. RNA-Seq identified differential expression of numerous matrisome genes including an 8.8-fold increase in Tgfb2 indicating myofibroblast activation. Further analysis suggests reprogramming of glycogen, ascorbic acid, and amino acid metabolism in support of collagen deposition and the use of proline as a substrate for ATP production via the proline cycle. In summary, we demonstrate that glycogen, ascorbic acid, and amino acid metabolism are also reorganized to support remodeling of the extracellular matrix, progressing to hepatic fibrosis in response to chronic injury from TCDD.

Topics: Animals; Ascorbic Acid; Cellular Reprogramming; Chemical and Drug Induced Liver Injury; Collagen; Cytokines; Dose-Response Relationship, Drug; Energy Metabolism; Extracellular Matrix; Female; Gene Expression Regulation; Glucose; Glycogen; Inflammation Mediators; Liver; Liver Cirrhosis; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease; Polychlorinated Dibenzodioxins; Proline; Time Factors; Transcriptome

The aim of the study was to evaluate lipid, cholesterol and glucose metabolism in a novel rat model of non-alcoholic fatty liver disease (NAFLD).. Rats (Wistar) were fed high fat/cholesterol diet (HFD) and a single low dose (35mg/kg) of streptozotocin (STZ). Collagen and glycogen content, oxidative stress and glucokinase activity were measured using biochemical assays. Other metabolic pathways were assessed by qRT-PCR.. HFD/STZ treated rats, compared to control ones, showed an increase in expression of biomarkers of inflammation (TNFα, IL6), fibrosis (TGFβ), mitochondrial stress (UCP2) and oxidative stress (GSH and carbonylated proteins) but not of ER stress (CHOP, XBP1). Additionally, HFD/STZ treatment caused a reduction in glycogen content, glucokinase activity (a limiting step in glycolysis) and expression of ChREBP gene (a de novo lipogenesis regulator), suggesting a modified glycolytic pathway. The cholesterol biosynthesis in HFD/STZ treated rats was inhibited (reduced expression of SREBP-2-regulated HMGCoA red and LDLr), instead the cholesterol catabolism was increased, as shown by the mRNA induction of the CYP7A1 and CYP8B1 (key genes for BA acid). A reduced gene expression of FXR-dependent SHP (a key gene for feedback inhibition of CYP7A1 and CYP8B1) and of bile acids (NTCP, OATP1A1, BSEP) and cholesterol (ABCA1) transporters was found.. These results widely extend the characterization of HFD/STZ rat model, which might mimic the NAFLD/NASH in diabetic humans.

Topics: Animals; Cholesterol; Diet, High-Fat; Gene Expression Regulation; Glucose; Glycogen; Lipid Metabolism; Liver; Male; Non-alcoholic Fatty Liver Disease; Rats, Wistar; Streptozocin

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

Nonalcoholic fatty liver disease (NAFLD) is a risk factor for type 2 diabetes (T2D), but whether NAFLD plays a causal role in the pathogenesis of T2D is uncertain. One proposed mechanism linking NAFLD to hepatic insulin resistance involves diacylglycerol-mediated (DAG-mediated) activation of protein kinase C-ε (PKCε) and the consequent inhibition of insulin receptor (INSR) kinase activity. However, the molecular mechanism underlying PKCε inhibition of INSR kinase activity is unknown. Here, we used mass spectrometry to identify the phosphorylation site Thr1160 as a PKCε substrate in the functionally critical INSR kinase activation loop. We hypothesized that Thr1160 phosphorylation impairs INSR kinase activity by destabilizing the active configuration of the INSR kinase, and our results confirmed this prediction by demonstrating severely impaired INSR kinase activity in phosphomimetic T1160E mutants. Conversely, the INSR T1160A mutant was not inhibited by PKCε in vitro. Furthermore, mice with a threonine-to-alanine mutation at the homologous residue Thr1150 (InsrT1150A mice) were protected from high fat diet-induced hepatic insulin resistance. InsrT1150A mice also displayed increased insulin signaling, suppression of hepatic glucose production, and increased hepatic glycogen synthesis compared with WT controls during hyperinsulinemic clamp studies. These data reveal a critical pathophysiological role for INSR Thr1160 phosphorylation and provide further mechanistic links between PKCε and INSR in mediating NAFLD-induced hepatic insulin resistance.

Topics: Amino Acid Substitution; Animals; Diabetes Mellitus, Type 2; Dietary Fats; Glycogen; Insulin Resistance; Liver; Mice; Mice, Mutant Strains; Mutation, Missense; Non-alcoholic Fatty Liver Disease; Phosphorylation; Protein Kinase C-epsilon; Receptor, Insulin; Signal Transduction

Non-alcoholic fatty liver disease (NAFLD) is a major health problem and occurs frequently in the context of metabolic syndrome and type 2 diabetes mellitus. Hepatocyte-specific Pten-deficiency in mice was shown previously to result in hepatic steatosis due to hyperactivated AKT2. However, the role of peripheral insulin-sensitive tissues on PTEN- and AKT2-dependent accumulation of hepatic lipids has not been addressed.. Effects of systemically perturbed PTEN/AKT2 signalling on hepatic lipid content were studied in Pten-haplodeficient (Pten(+/-) /Akt2(+/+) ) mice and Pten-haplodeficient mice lacking Akt2 (Pten(+/-) /Akt2(-/-) ). The liver and skeletal muscle were characterized by histology and/or analysis of insulin signalling. To assess the effects of AKT2 activity in skeletal muscle on hepatic lipid content, AKT2 mutants were expressed in skeletal muscle of Pten(+/+) /Akt2(+/+) and Pten(+/-) /Akt2(+/+) mice using adeno-associated virus 8.. Pten(+/-) /Akt2(+/+) mice were found to have a more than 2-fold reduction in hepatic lipid content, at a level similar to that observed in Pten(+/-) /Akt2(-/-) mice. Insulin signalling in the livers of Pten(+/-) /Akt2(+/+) mice was enhanced, indicating that extrahepatic factors prevent lipid accumulation. The skeletal muscle of Pten(+/-) /Akt2(+/+) mice also showed enhanced insulin signalling. Skeletal muscle-specific expression of constitutively active AKT2 reduced hepatic lipid content in Pten(+/+) /Akt2(+/+) mice, and dominant negative AKT2 led to an increase in accumulation of hepatic lipids in both Pten(+/+) /Akt2(+/+) and Pten(+/-) /Akt2(+/+) mice.. Our results demonstrate that AKT2 activity in skeletal muscle critically affects lipid accumulation in the livers of Pten(+/+) /Akt2(+/+) and Pten(+/-) /Akt2(+/+) mice, and emphasize the role of skeletal muscle in the pathology of NAFLD.

Topics: Animals; Blood Glucose; Disease Models, Animal; Enzyme Activation; Genotype; Glycogen; Haploinsufficiency; Insulin; Lipid Metabolism; Liver; Male; Mice, Inbred C57BL; Mice, Knockout; Muscle, Skeletal; Mutation; Non-alcoholic Fatty Liver Disease; Phenotype; Proto-Oncogene Proteins c-akt; PTEN Phosphohydrolase; Signal Transduction; Time Factors

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

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

To investigate whether alpha-lipoic acid (ALA) could attenuate the insulin resistance and metabolic disorders in high fat diet-fed mice.. Male mice were fed a high fat diet (HFD) plus ALA (100 and 200 mg·kg(-1)·d(-1)) or HFD plus a positive control drug metformin (300 mg·kg(-1)·d(-1)) for 24 weeks. During the treatments, the relevant physiological and metabolic parameters of the mice were measured. After the mice were euthanized, blood samples and livers were collected. The expression of proteins and genes related to glucose metabolism in livers were analyzed by immunoblotting and real time-PCR.. HFD induced non-alcoholic fatty liver disease (NAFLD) and abnormal physiological and metabolic parameters in the mice, which were dose-dependently attenuated by ALA. ALA also significantly reduced HFD-induced hyperglycemia and insulin resistance in HFD-fed mice. Furthermore, ALA significantly upregulated the glycolytic enzymes GCK, HK-1 and PK, and the glycogen synthesis enzyme GS, and downregulated the gluconeogenic enzymes PEPCK and G6Pase, thus decreased glucose production, and promoted glycogen synthesis and glucose utilization in livers. Moreover, ALA markedly increased PKB/Akt and GSK3β phosphorylation, and nuclear carbohydrate response element binding protein (ChREBP) expression in livers. Metformin produced similar effects as ALA in HFD-fed mice.. ALA is able to sustain glucose homeostasis and prevent the development of NAFLD in HFD-fed mice.

Topics: Animals; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; Diet, High-Fat; Down-Regulation; Gluconeogenesis; Glucose; Glycogen; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Glycolysis; Hyperglycemia; Insulin Resistance; Liver; Male; Metabolic Diseases; Mice; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease; Nuclear Proteins; Proto-Oncogene Proteins c-akt; Thioctic Acid; Transcription Factors; Up-Regulation

Topics: Adolescent; Child; Diabetes Mellitus, Type 1; Female; Glycogen; Humans; Liver Diseases; Male; Non-alcoholic Fatty Liver Disease; Tomography, X-Ray Computed

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

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