4-hydroxy-2-nonenal and Fatty-Liver

The role of zinc (Zn) in hepatic steatosis of patients with HCV-related chronic liver disease (CLD-C) remains uncertain, although persistent HCV infection often evokes hepatic steatosis. The primary purpose of this study was to elucidate the contribution of Zn deficiency to hepatic steatosis in patients with CLD-C. Fifty nondiabetic patients with CLD-C were enrolled. Hepatic 4-hydroxy-2-nonenal (4-HNE) expression was examined using an immunohistochemical procedure as a marker for lipid peroxidation. Serum ferritin levels were assessed for iron overload. Insulin resistance was evaluated using the values of the homeostasis model for assessment of insulin resistance (HOMA-IR). The severity of hepatic steatosis was graded on the classification system proposed by Brunt and colleagues. Serum Zn levels were inversely correlated with serum ferritin levels in the patients with CLD-C (r = -0.382, p = 0.0062). Serum ferritin levels were strongly associated with the HOMA-IR values (r = 0.476, p = 0.0005). Therefore, Zn deficiency resulted in insulin resistance through iron overload. Moreover, serum Zn levels were significantly decreased in proportion to the level of hepatic 4-HNE expression, which was enhanced as hepatic steatosis developed. Then, Zn deficiency eventually seemed to exacerbate hepatic steatosis by way of an increase in lipid peroxidation. However, the serum Zn levels were not associated with either loads of HCV-RNA or HCV genotypes. These data suggest that, in patients with CLD-C, Zn deficiency promotes insulin resistance by exacerbating iron overload in the liver and induces hepatic steatosis by facilitating lipid peroxidation.

Topics: Adult; Aged; Aldehydes; Fatty Liver; Female; Ferritins; Hepatitis C, Chronic; Humans; Insulin Resistance; Lipid Peroxidation; Liver; Male; Middle Aged; Zinc

Previous work with metformin has shown that this antidiabetic agent improves nonalcoholic fatty liver in ob/ob mice. AMP-activated protein kinase (AMPK) is one of the major cellular regulators of lipid and glucose metabolism, and reportedly mediates the beneficial metabolic effects of metformin. In this study, we examined the effects of 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR), an AMPK activator, on an experimental model of ethanol-induced hepatic steatosis.. Rats were randomly divided into three groups: (A) rats fed ethanol-containing liquid diet for six weeks; (B) rats pair-fed ethanol-containing liquid diet for six weeks, during the last three weeks of which they were subcutaneously injected with 0.5 mg AICAR/g body weight per day; (C) rats pair-fed isocaloric liquid diet without ethanol for six weeks. At the end of the six-week period, the animals were sacrificed. Serum and liver specimens were analyzed using biochemical and histologic methods, as well as real-time PCR.. Chronic ethanol feeding resulted in fatty liver both histologically and biochemically, whereas AICAR administration attenuated the degree of change in the liver. AICAR also decreased the hepatic sterol regulatory factor binding protein-1c (SREBP-1c) and reduced fatty acid synthase (FAS) expression; these changes led to reduced triglyceride synthesis in rat livers. Furthermore, detection of 4-hydroxy-2-nonenal (4-HNE)-protein adducts showed that the AICAR treatment also decreased the products of lipid peroxidation.. In this preclinical rat model, AICAR, an AMPK activator, appears to protect the liver from fatty changes associated with chronic alcohol use. As such, AICAR may have a role in the treatment and prevention of alcohol-induced fatty liver.

Topics: Aldehydes; Aminoimidazole Carboxamide; AMP-Activated Protein Kinases; Animals; Central Nervous System Depressants; Cysteine Proteinase Inhibitors; Enzyme Activators; Ethanol; Fatty Acid Synthases; Fatty Liver; Immunohistochemistry; Lipid Peroxidation; Liver; Male; Multienzyme Complexes; Protein Serine-Threonine Kinases; Rats; Rats, Wistar; Reverse Transcriptase Polymerase Chain Reaction; Ribonucleotides; Sterol Regulatory Element Binding Protein 1; Triglycerides

Obesity and type 2 diabetes have reached pandemic proportion. ALDH2 (acetaldehyde dehydrogenase 2, mitochondrial) is the key metabolizing enzyme of acetaldehyde and other toxic aldehydes, such as 4-hydroxynonenal. A missense Glu504Lys mutation of the ALDH2 gene is prevalent in 560 million East Asians, resulting in reduced ALDH2 enzymatic activity. We find that male Aldh2 knock-in mice mimicking human Glu504Lys mutation were prone to develop diet-induced obesity, glucose intolerance, insulin resistance, and fatty liver due to reduced adaptive thermogenesis and energy expenditure. We find reduced activity of ALDH2 of the brown adipose tissue from the male Aldh2 homozygous knock-in mice. Proteomic analyses of the brown adipose tissue from the male Aldh2 knock-in mice identifies increased 4-hydroxynonenal-adducted proteins involved in mitochondrial fatty acid oxidation and electron transport chain, leading to markedly decreased fatty acid oxidation rate and mitochondrial respiration of brown adipose tissue, which is essential for adaptive thermogenesis and energy expenditure. AD-9308 is a water-soluble, potent, and highly selective ALDH2 activator. AD-9308 treatment ameliorates diet-induced obesity and fatty liver, and improves glucose homeostasis in both male Aldh2 wild-type and knock-in mice. Our data highlight the therapeutic potential of reducing toxic aldehyde levels by activating ALDH2 for metabolic diseases.

Topics: Aldehyde Dehydrogenase; Aldehyde Dehydrogenase, Mitochondrial; Animals; Diabetes Mellitus, Type 2; Fatty Acids; Fatty Liver; Humans; Male; Mice; Mutation; Obesity; Proteomics

Topics: Acetyl-CoA Carboxylase; Aldehydes; AMP-Activated Protein Kinases; Animals; Chemical and Drug Induced Liver Injury, Chronic; Corn Oil; Ethanol; Fatty Acids; Fatty Acids, Omega-6; Fatty Liver; Liver; Male; Mice; Mice, Inbred C57BL; Palm Oil; Sterol Regulatory Element Binding Protein 1; Triglycerides; Up-Regulation

Curcumin, an antioxidant compound found in Asian spices, was evaluated for its protective effects against ethanol-induced hepatosteatosis, liver injury, antiatherogenic markers, and antioxidant status in rats fed with Lieber-deCarli low menhaden (2.7% of total calories from ω-3 polyunsaturated fatty acids (PUFA)) and Lieber-deCarli high menhaden (13.8% of total calories from ω-3 PUFA) alcohol-liquid (5%) diets supplemented with or without curcumin (150 mg/kg/day) for 8 weeks. Treatment with curcumin protected against high ω-3 PUFA and ethanol-induced hepatosteatosis and increase in liver injury markers, alanine aminotransferase, and aspartate aminotransferase. Curcumin upregulated paraoxonase 1 (PON1) mRNA and caused significant increase in serum PON1 and homocysteine thiolactonase activities as compared to high ω-3 PUFA and ethanol group. Moreover, treatment with curcumin protected against ethanol-induced oxidative stress by increasing the antioxidant glutathione and decreasing the lipid peroxidation adduct 4-hydroxynonenal. These results strongly suggest that chronic ethanol in combination with high ω-3 PUFA exacerbated hepatosteatosis and liver injury and adversely decreases antiatherogenic markers due to increased oxidative stress and depletion of glutathione. Curcumin supplementation significantly prevented these deleterious actions of chronic ethanol and high ω-3 PUFA. Therefore, we conclude that curcumin may have therapeutic potential to protect against chronic alcohol-induced liver injury and atherosclerosis.

Topics: Aldehydes; Animals; Antioxidants; Aryldialkylphosphatase; Atherosclerosis; Biomarkers; Chemical and Drug Induced Liver Injury; Curcumin; Diet; Ethanol; Fatty Acids, Omega-3; Fatty Liver; Female; Glutathione; Lipid Metabolism; Lipid Peroxidation; Oxidative Stress; Rats; Rats, Wistar

Overproduction of reactive oxygen species is associated with the development of alcoholic liver disease (ALD). Plant polyphenols have been used as dietary interventions for multiple diseases including ALD. The objective of this study was to determine whether dietary supplementation with fisetin, a novel flavonoid, exerts beneficial effect on alcohol-induced liver injury.. C57BL/6J mice were pair-fed with the Lieber-DeCarli control or ethanol (EtOH) diet for 4 weeks with or without fisetin supplementation at 10 mg/kg/d.. Alcohol feeding induced lipid accumulation in the liver and increased plasma alanine aminotransferase and aspartate aminotransferase activities, which were attenuated by fisetin supplementation. The EtOH concentrations in the plasma and liver were significantly elevated by alcohol exposure but were reduced by fisetin supplementation. Although fisetin did not affect the protein expression of alcohol metabolism enzymes, the aldehyde dehydrogenase activities were significantly increased by fisetin compared to the alcohol alone group. In addition, fisetin supplementation remarkably reduced hepatic NADPH oxidase 4 levels along with decreased plasma hydrogen peroxide and hepatic superoxide and 4-hydroxynonenal levels after alcohol exposure. Alcohol-induced apoptosis and up-regulation of Fas and cleaved caspase-3 in the liver were prevented by fisetin. Moreover, fisetin supplementation attenuated alcohol-induced hepatic steatosis through increasing plasma adiponectin levels and hepatic protein levels of p-AMPK, ACOX1, CYP4A, and MTTP.. This study demonstrated that the protective effect of fisetin on ALD is achieved by accelerating EtOH clearance and inhibition of oxidative stress. The data suggest that fisetin has a therapeutical potential for treating ALD.

Topics: Acyl-CoA Oxidase; Adiponectin; Aldehyde Dehydrogenase; Aldehydes; AMP-Activated Protein Kinases; Animals; Apoptosis; Carrier Proteins; Cytochrome P-450 CYP4A; Dietary Supplements; Ethanol; Fatty Liver; Flavonoids; Flavonols; Hydrogen Peroxide; Liver; Liver Diseases, Alcoholic; Male; Mice; NADPH Oxidase 4; Protective Agents; Superoxides; Up-Regulation

The aim of the present study was to assess whether the effects of acute consumption of stout or pilsner beer on the liver differ from those of plain ethanol in a mouse model.. Seven-week-old female C57BL/6J mice received either ethanol, stout or pilsner beer (ethanol content: 6 g/kg body weight) or isocaloric maltodextrin solution. Plasma alanine transaminase, markers of steatosis, lipogenesis, activation of the toll-like receptor-4 signaling cascade as well as lipid peroxidation and fibrogenesis in the liver were measured 12 h after acute ethanol or beer intake.. Acute alcohol ingestion caused a marked ~11-fold increase in hepatic triglyceride accumulation in comparison to controls, whereas in mice exposed to stout and pilsner beer, hepatic triglyceride levels were increased only by ~6.5- and ~4-fold, respectively. mRNA expression of sterol regulatory element-binding protein 1c and fatty acid synthase in the liver did not differ between alcohol and beer groups. In contrast, expression of myeloid differentiation primary response gene 88, inducible nitric oxide synthases, but also the concentrations of 4-hydroxynonenal protein adducts, nuclear factor κB and plasminogen activator inhibitor-1 were induced in livers of ethanol treated mice but not in those exposed to the two beers.. Taken together, our results suggest that acute ingestion of beer and herein especially of pilsner beer is less harmful to the liver than the ingestion of plain ethanol.

Topics: Alanine Transaminase; Aldehydes; Animals; Beer; Biomarkers; Disease Models, Animal; Ethanol; Fatty Liver; Female; Lipid Peroxidation; Lipogenesis; Liver; Mice; Mice, Inbred C57BL; Myeloid Differentiation Factor 88; NF-kappa B; Nitric Oxide Synthase Type II; Plasminogen Activator Inhibitor 1; Polysaccharides; RAW 264.7 Cells; RNA, Messenger; Sterol Regulatory Element Binding Protein 1; Toll-Like Receptor 4; Triglycerides

The production of reactive aldehydes including 4-hydroxy-2-nonenal (4-HNE) is a key component of the pathogenesis in a spectrum of chronic inflammatory hepatic diseases including alcoholic liver disease (ALD). One consequence of ALD is increased oxidative stress and altered β-oxidation in hepatocytes. A major regulator of β-oxidation is 5' AMP protein kinase (AMPK). In an in vitro cellular model, we identified AMPK as a direct target of 4-HNE adduction resulting in inhibition of both H2O2 and 5-aminoimidazole-4-carboxyamide ribonucleoside (AICAR)-induced downstream signaling. By employing biotin hydrazide capture, it was confirmed that 4-HNE treatment of cells resulted in carbonylation of AMPKα/β, which was not observed in untreated cells. Using a murine model of alcoholic liver disease, treatment with high concentrations of ethanol resulted in an increase in phosphorylated as well as carbonylated AMPKα. Despite increased AMPK phosphorylation, there was no significant change in phosphorylation of acetyl CoA carboxylase. Mass spectrometry identified Michael addition adducts of 4-HNE on Cys(130), Cys(174), Cys(227), and Cys(304) on recombinant AMPKα and Cys(225) on recombinant AMPKβ. Molecular modeling analysis of identified 4-HNE adducts on AMPKα suggest that inhibition of AMPK occurs by steric hindrance of the active site pocket and by inhibition of hydrogen peroxide induced oxidation. The observed inhibition of AMPK by 4-HNE provides a novel mechanism for altered β-oxidation in ALD, and these data demonstrate for the first time that AMPK is subject to regulation by reactive aldehydes in vivo.

Topics: Aldehydes; AMP-Activated Protein Kinases; Animals; Central Nervous System Depressants; Cysteine Proteinase Inhibitors; Disease Models, Animal; Ethanol; Fatty Liver; Hep G2 Cells; Humans; Lipid Peroxidation; Liver Diseases, Alcoholic; Male; Mice; Mice, Inbred C57BL; Models, Chemical; Oxidative Stress; Phosphorylation; Protein Carbonylation; Signal Transduction

Consumption of a high-fructose diet (HFrD) can induce the development of a metabolic syndrome, manifesting as nonalcoholic steatohepatitis (NASH) and/or type 2 diabetes mellitus (T2DM), via a process in which oxidative stress plays a critical role. Peroxiredoxin 4 (PRDX4) is a unique and only known secretory member of the PRDX antioxidant family. However, its putative roles in the development of NASH and/or T2DM have not been investigated.. To elucidate the functions of PRDX4 in a metabolic syndrome, we established a nongenetic mouse model of T2DM by feeding mice a HFrD after injecting a relatively low dose of streptozotocin. Compared with wild-type (WT), human PRDX4 transgenic (Tg) mice exhibited significant improvements in insulin resistance, characterized by a lower glucose and insulin concentration and faster responses in glucose tolerance tests. The liver of Tg also showed less severe vesicular steatosis, inflammation, and fibrosis, along with lower lipid concentrations, lower levels of oxidative stress markers, more decreased expression of hepatic aminotransferase, and more reduced stellate cell activation than those in the WT liver, reminiscent of human early NASH. Hepatocyte apoptosis was also significantly repressed in Tg mice. By contrast, serum adiponectin levels and hepatic adiponectin receptor expression were significantly lower in WT mice, consistent with greater insulin resistance in the peripheral liver tissue compared with Tg mice.. Our data for the first time show that PRDX4 may protect against NASH, T2DM, and the metabolic syndrome by ameliorating oxidative stress-induced injury.

Topics: Adiponectin; Aldehydes; Animals; Apoptosis; Cells, Cultured; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Disease Models, Animal; Fatty Liver; Guanosine; Hepatocytes; Humans; Inflammation Mediators; Liver; Male; Mice; Mice, Transgenic; Non-alcoholic Fatty Liver Disease; Oxidative Stress; Peroxiredoxins; Receptors, Adiponectin; T-Lymphocytes; Thiobarbituric Acid Reactive Substances

The rate of onset of hepatocellular carcinoma (HCC) in patients with nonalcoholic steatohepatitis (NASH) has been reported recently to be comparable to that of patients with chronic hepatitis C. However, the precise mechanism contributing to carcinogenesis in the former remains unclear. Although increased oxidative stress is presumed to play a role in carcinogenesis in patients with NASH, this relationship remains to be directly proven. In this study, we investigated the involvement of oxidative DNA damage in hepatocarcinogenesis in patients with NASH.. Patients with nonalcoholic fatty liver disease who were treated at our university hospital were eligible for enrolment in the study(n = 49). The study cohort included 30 patients with NASH without HCC (NASH without HCC), six HCC patients with NASH (NASH-HCC), and 13 patients with simple steatosis. Quantitative immunohistochemistry with a KS-400 image analyzing system was used for 8-hydroxy-2'-deoxyguanosine (8-OHdG) detection.. The 8-OHdG content in the liver tissue of NASH-HCC patients was significantly different from that in the other patients. The median immunostaining intensity was 8.605 in the NASH-HCC cases, which was significantly higher than that in the cases of NASH without HCC (4.845; P = 0.003). Multivariate analysis using hepatic 8-OHdG content as a factor in addition to age and fasting blood sugar revealed a significant difference in clinicopathological factors between NASH-HCC and NASH without HCC cases. Old age (P = 0.015) and high relative immunostaining intensity for intrahepatic 8-OHdG (P = 0.037) were identified as independent factors.. 8-OHdG content in liver tissue may serve a marker of oxidative stress and could be a particularly useful predictor of hepatocarcinogenesis.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Aged; Aged, 80 and over; Aldehydes; Carcinoma, Hepatocellular; Cell Transformation, Neoplastic; Deoxyguanosine; DNA Damage; DNA, Neoplasm; Fatty Liver; Female; Humans; Liver; Liver Neoplasms; Male; Middle Aged; Neoplasm Staging; Non-alcoholic Fatty Liver Disease; Oxidative Stress; Young Adult

Oxidative and nitrative stress responses resulting from inflammation exacerbate liver injury associated with nonalcoholic steatohepatitis (NASH) by inducing lipid peroxidation and protein nitration. The objective of this study was to investigate whether the anti-inflammatory properties of green tea extract (GTE) would protect against NASH by suppressing oxidative and nitrative damage mediated by proinflammatory enzymes. Obese mice (ob/ob) and their 5-week-old C57BL6 lean littermates were fed 0%, 0.5% or 1% GTE for 6 weeks (n=12-13 mice/group). In obese mice, hepatic lipid accumulation, inflammatory infiltrates and serum alanine aminotransferase activity were markedly increased, whereas these markers of hepatic steatosis, inflammation and injury were significantly reduced among obese mice fed GTE. GTE also normalized hepatic 4-hydroxynonenal and 3-nitro-tyrosine (N-Tyr) concentrations to those observed in lean controls. These oxidative and nitrative damage markers were correlated with alanine aminotransferase (P<.05; r=0.410-0.471). Improvements in oxidative and nitrative damage by GTE were also associated with lower hepatic nicotinamide adenine dinucleotide phosphate oxidase activity. Likewise, GTE reduced protein expression levels of hepatic myeloperoxidase and inducible nitric oxide synthase and decreased the concentrations of nitric oxide metabolites. Correlative relationships between nicotinamide adenine dinucleotide phosphate oxidase and hepatic 4-hydroxynonenal (r=0.364) as well as nitric oxide metabolites and N-Tyr (r=0.598) suggest that GTE mitigates lipid peroxidation and protein nitration by suppressing the generation of reactive oxygen and nitrogen species. Further study is warranted to determine whether GTE can be recommended as an effective dietary strategy to reduce the risk of obesity-triggered NASH.

Topics: Alanine Transaminase; Aldehydes; Animals; Anti-Inflammatory Agents; Fatty Liver; Inflammation; Lipid Peroxidation; Liver; Male; Mice; Mice, Inbred C57BL; Mice, Obese; NADPH Oxidases; Nitric Oxide Synthase Type II; Non-alcoholic Fatty Liver Disease; Obesity; Oxidative Stress; Peroxidase; Plant Extracts; Reactive Oxygen Species; Stress, Physiological; Tea; Tyrosine

Type 2 diabetes mellitus (T2DM) is a well-known factor risk for non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) in obese patients.. To better understand the association between T2DM and NAFLD, global changes in protein expression in diabetic and non-diabetic obese subjects were assessed by a proteomic approach.. Liver samples were obtained from diabetic and non-diabetic morbid obese subjects (BMI>40 kg/m(2) ). Histological analysis was used to evaluate hepatic steatosis and the degree of anatomopathological alteration. Changes in protein expression were analysed by two-dimentional electrophoresis combined with MALDI-TOF mass spectrometry. Levels of glutathione, carbonyl and 4-HNE protein adducts were used to assess oxidative stress status.. Of 850 proteins analysed, 33 were differentially expressed in T2DM obese subjects. Of these, 27 were unequivocally identified by mass spectrometry. Analysis of protein sets revealed patterns of decreased abundance in mitochondrial enzymes, proteins involved in methione metabolism, and oxidative stress response. Accordingly, T2DM subjects showed decreased levels of glutathione, the antioxidant byproduct of methionine metabolism via the transsulfuration pathway, and higher levels of protein and lipid oxidative damage. Changes in detoxyfing enzymes, carbohydrate metabolism, proteasome subunits and retinoic acid synthesis were also found.. The results suggest alterations in mitochondrial function and methionine metabolism as potential contributing factors to increased oxidative stress in liver of obese diabetic patients which may be influencing the development of NAFLD and NASH.

Topics: Adult; Aldehydes; Biomarkers; Biopsy; Diabetes Mellitus, Type 2; Electrophoresis, Gel, Two-Dimensional; Fatty Liver; Female; Glutathione; Humans; Liver; Methionine; Middle Aged; Mitochondria, Liver; Non-alcoholic Fatty Liver Disease; Obesity, Morbid; Oxidative Stress; Protein Carbonylation; Proteins; Proteomics; Severity of Illness Index; Spain; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization

Insulin resistance, oxidative stress, inflammation and innate immune system activation contribute to the development of non-alcoholic fatty liver disease (NAFLD) through steatosis and inflammation in the liver. The powerful antioxidant α-lipoic acid (ALA) has been shown to improve insulin sensitivity and suppress inflammatory responses. This study explores how ALA administration protects against NAFLD.. Otsuka Long-Evans Tokushima Fatty (OLETF) rats were divided into two groups (treated with 200 mg/kg/day of ALA or untreated) at 12 weeks of age and sacrificed at 28 weeks of age.. Serum levels of insulin, free fatty acids, total cholesterol, triglyceride, leptin, IL-6 and blood glucose were decreased in ALA-treated rats. Serum adiponectin levels were higher in ALA-treated rats. ALA treatment decreased the expression of sterol regulatory element binding protein-1 and acetyl CoA carboxylase, and increased glucose transporter-4 expression in the livers of OLETF rats. Expression of the antioxidant enzymes heme oxygenase-1 and Cu/Zn-superoxide dismutase was increased in the livers of ALA-treated rats. The lipid peroxidation marker 4-hydroxynonenal was decreased in the liver of ALA-treated rats. Proteins associated with innate immune activation (Toll-like receptor-4 and high-mobility group protein box-1) and inflammatory markers (vascular cell adhesion molecule-1, intercellular adhesion molecule-1, and cyclooxygenase-2) were decreased in the livers of ALA-treated rats.. Chronic ALA supplementation prevents NAFLD through multiple mechanisms by reducing steatosis, oxidative stress, immune activation and inflammation in the liver.

Topics: Acetyl-CoA Carboxylase; Adiponectin; Aldehydes; Animals; Azo Compounds; Blood Glucose; Blotting, Western; Cholesterol; Cyclooxygenase 2; Fatty Acids; Fatty Liver; Fluorescent Antibody Technique; Gene Expression Regulation; Glucose Transporter Type 4; Immunity, Innate; Immunohistochemistry; Insulin; Intercellular Adhesion Molecule-1; Interleukin-6; Leptin; Lipid Peroxidation; Liver; Non-alcoholic Fatty Liver Disease; Rats; Rats, Inbred OLETF; Sterol Regulatory Element Binding Protein 1; Thioctic Acid; Toll-Like Receptor 4; Triglycerides; Vascular Cell Adhesion Molecule-1

As significant differences between sexes were found in the susceptibility to alcoholic liver disease in human and animal models, it was the aim of the present study to investigate whether female mice also are more susceptible to the development of non-alcoholic fatty liver disease (NAFLD). Male and female C57BL/6J mice were fed either water or 30% fructose solution ad libitum for 16 wks. Liver damage was evaluated by histological scoring. Portal endotoxin levels and markers of Kupffer cell activation and insulin resistance, plasminogen activator inhibitor 1 (PAI-1) and phosphorylated adenosine monophosphate-activated protein kinase (pAMPK ) were measured in the liver. Adiponectin mRNA expression was determined in adipose tissue. Hepatic steatosis was almost similar between male and female mice; however, inflammation was markedly more pronounced in livers of female mice. Portal endotoxin levels, hepatic levels of myeloid differentiation primary response gene (88) (MyD88) protein and of 4-hydroxynonenal protein adducts were elevated in animals with NAFLD regardless of sex. Expression of insulin receptor substrate 1 and 2 was decreased to a similar extent in livers of male and female mice with NAFLD. The less pronounced susceptibility to liver damage in male mice was associated with a superinduction of hepatic pAMPK in these mice whereas, in livers of female mice with NAFLD, PAI-1 was markedly induced. Expression of adiponectin in visceral fat was significantly lower in female mice with NAFLD but unchanged in male mice compared with respective controls. In conclusion, our data suggest that the sex-specific differences in the susceptibility to NAFLD are associated with differences in the regulation of the adiponectin-AMPK-PAI-1 signaling cascade.

Topics: Adiponectin; Aldehydes; AMP-Activated Protein Kinases; Animals; Disease Susceptibility; Endotoxins; Energy Intake; Fatty Liver; Female; Fructose; Humans; Inflammation; Insulin; Intramolecular Oxidoreductases; Lipid Metabolism; Liver; Male; Mice; Non-alcoholic Fatty Liver Disease; Phosphorylation; Plasminogen Activator Inhibitor 1; Prostaglandin-E Synthases; Receptors, Adiponectin; Sex Characteristics; Signal Transduction; Toll-Like Receptor 4; Tumor Necrosis Factor-alpha; Weight Gain

To test the hypothesis that the inducible nitric oxide synthase (iNOS) is involved in mediating the toll-like receptor 4-dependent effects on the liver in the onset of fructose-induced steatosis, wild-type and iNOS knockout (iNOS(-/-)) mice were either fed tap water or 30% fructose solution for 8 weeks. Chronic consumption of 30% fructose solution led to a significant increase in hepatic steatosis and inflammation as well as plasma alanine-aminotransferase levels in wild-type mice. This effect of fructose feeding was markedly attenuated in iNOS(-/-) mice. Hepatic lipidperoxidation, concentration of phospho-IκB, nuclear factor κB activity, and tumor necrosis factor-α mRNA level were significantly increased in fructose-fed wild-type mice, whereas in livers of fructose-fed iNOS(-/-) mice, lipidperoxidation, phospho-IκB, nuclear factor κB activity, and tumor necrosis factor-α expression were almost at the level of controls. However, portal endotoxin levels and hepatic myeloid differentiation factor 88 expression were significantly higher in both fructose-fed groups compared to controls. Taken together, these data suggest that (i) the formation of reactive oxygen species in liver is a key factor in the onset of fatty liver and (ii) iNOS is involved in mediating the endotoxin/toll-like receptor 4-dependent effects in the development of fructose-induced fatty liver.

Topics: Aldehydes; Animals; Cells, Cultured; Coculture Techniques; Endotoxins; Fatty Liver; Fructokinases; Fructose; Glutathione; I-kappa B Proteins; Insulin Resistance; Kupffer Cells; Lipid Peroxidation; Liver; Mice; Mice, Inbred C57BL; Mice, Knockout; Myeloid Differentiation Factor 88; NF-kappa B; Nitric Oxide Synthase Type II; Organ Size; Toll-Like Receptor 4; Transcription, Genetic; Triglycerides; Tumor Necrosis Factor-alpha; Tyrosine; Weight Gain

Elevated dietary fructose intake, altered intestinal motility, and barrier function may be involved in the development of nonalcoholic fatty liver disease (NAFLD). Because intestinal motility and permeability are also regulated through the bioavailability of serotonin (5-HT), we assessed markers of hepatic injury in serotonin reuptake transporter knockout (SERT(-/-)) and wild-type mice chronically exposed to different monosaccharide solutions (30% glucose or fructose solution) or water for 8 wk. The significant increase in hepatic triglyceride, TNF-alpha, and 4-hydroxynonenal adduct as well as portal endotoxin levels found in fructose-fed mice was associated with a significant decrease of SERT and the tight-junction occludin in the duodenum. Similar effects were not found in mice fed glucose. In contrast, in SERT(-/-) mice fed glucose, portal endotoxin levels, concentration of occludin, and indices of hepatic damage were similar to those found in wild-type and SERT(-/-) mice fed fructose. In fructose-fed mice treated with a 5-HT3 receptor antagonist, hepatic steatosis was significantly attenuated. Our data suggest that a loss of intestinal SERT is a critical factor in fructose-induced impairment of intestinal barrier function and subsequently the development of steatosis.

Topics: Aldehydes; Animals; Body Weight; Caco-2 Cells; Duodenum; Endotoxins; Fatty Liver; Fructose; Gastrointestinal Motility; Gene Expression; Glucose; Humans; Indoles; Intestinal Absorption; Liver; Membrane Proteins; Mice; Mice, Inbred C57BL; Mice, Transgenic; Models, Biological; Neutrophils; Occludin; Organ Size; Permeability; Serotonin; Serotonin Antagonists; Serotonin Plasma Membrane Transport Proteins; Triglycerides; Tropisetron; Tumor Necrosis Factor-alpha

Both insulin resistance and increased oxidative stress in the liver are associated with the pathogenesis of nonalcoholic fatty liver disease (NAFLD). Senescence marker protein-30 (SMP30) was initially identified as a novel protein in the rat liver, and acts as an antioxidant and antiapoptotic protein. Our aim was to determine whether hepatic SMP30 levels are associated with the development and progression of NAFLD.. Liver biopsies and blood samples were obtained from patients with an NAFLD activity score (NAS) < or = 2 (n = 18), NAS of 3-4 (n = 14), and NAS > or = 5 (n = 66).. Patients with NAS > or = 5 had significantly lower hepatic SMP30 levels (12.5 +/- 8.4 ng/mg protein) than patients with NAS < or = 2 (30.5 +/- 14.2 ng/mg protein) and patients with NAS = 3-4 (24.6 +/- 12.2 ng/mg protein). Hepatic SMP30 decreased in a fibrosis stage-dependent manner. Hepatic SMP30 levels were correlated positively with the platelet count (r = 0.291) and negatively with the homeostasis model assessment of insulin resistance (r = -0.298), the net electronegative charge modified-low-density lipoprotein (r = -0.442), and type IV collagen 7S (r = -0.350). The immunostaining intensity levels of 4-hydroxynonenal in the liver were significantly and inversely correlated with hepatic SMP30 levels. Both serum large very low-density lipoprotein (VLDL) and very small low-density lipoprotein (LDL) levels in patients with NAS > or = 5 were significantly higher than those seen in patients with NAS < or = 2, and these lipoprotein fractions were significantly and inversely correlated with hepatic SMP30.. These results suggest that hepatic SMP30 is closely associated with the pathogenesis of NAFLD, although it is not known whether decreased hepatic SMP30 is a result or a cause of cirrhosis.

Topics: Adult; Aged; Aldehydes; Calcium-Binding Proteins; Cholesterol, LDL; Cholesterol, VLDL; Disease Progression; Fatty Liver; Female; Homeostasis; Humans; Insulin Resistance; Intracellular Signaling Peptides and Proteins; Liver; Liver Cirrhosis; Male; Middle Aged; Platelet Count

Oxidative stress may play an important role in the pathogenesis of non-alcoholic steatohepatitis (NASH). Oleuropein, the active constituent of olive leaf, possesses anti-oxidant, hypoglycaemic, and hypolipidaemic activities. We aimed to investigate the preventive effects of olive leaf extract on hepatic fat accumulation in a rat model of NASH.. Spontaneously hypertensive/NIH-corpulent rats were fed a diet of AIN-93G with or without olive leaf extract (500, 1000, 2000 mg/kg diet, and control; 5 rats each) for 23 weeks. Serological and histopathological findings, anti-oxidative activity, and the alteration of fatty acid synthesis in the liver were evaluated.. Histopathologically, a diet of AIN-93G containing more than 1000 mg/kg olive leaf extract had a preventive effect for the occurrence of NASH. Thioredoxin-1 expression in the liver was more evident in rats fed this diet, and 4-hydroxynonenal expression in the liver was less evident in these rats. There were no significant differences in the activities of hepatic carnitine palmitoyltransferase, fatty acid synthase, malic enzyme, and phosphatidic acid phosphohydrolase among the groups.. Our data suggest that olive leaf extract may help prevent NASH, presumably through its anti-oxidative activity.

Topics: Aldehydes; Animal Feed; Animals; Antioxidants; Blood Chemical Analysis; Disease Models, Animal; Fatty Liver; Iridoid Glucosides; Iridoids; Liver; Male; Olea; Organ Size; Oxidative Stress; Plant Leaves; Pyrans; Rats; Rats, Inbred SHR; Thioredoxins

Non-alcoholic steatohepatitis is associated with the deposition of lipid droplets in the liver, and is characterised histologically by the infiltration of inflammatory cells, hepatocellular degeneration and liver fibrosis. Oxidative stress may play an important role in the onset and deterioration of non-alcoholic steatohepatitis. We previously reported that an Eriobotrya japonica seed extract, extracted in 70% ethanol, exhibited antioxidant actions in vitro and in vivo. In this study, we examined the effect of this extract in a rat model of non-alcoholic steatohepatitis.. The seed extract was given in the drinking water to fats being fed a methionine-choline-deficient diet for 15 weeks.. Increases in alanine aminotransferase and aspartate aminotransferase levels were significantly inhibited in rats fed the seed extract compared with the group on the diet alone. Formation of fatty droplets in the liver was also inhibited. Antioxidant enzyme activity in liver tissue was higher than in the diet-only group and lipid peroxidation was reduced compared with rats that also received the extract. Expression of 8-hydroxy-2'-deoxyguanosine and 4-hydroxy-2-nonenal was lower in the rats given the seed extract than in the diet-only group. In the former, liver tissue levels of transforming growth factor-beta and collagen were also decreased.. Thus, the E. japonica seed extract inhibited fatty liver, inflammation and fibrosis, suggesting its usefulness in the treatment of non-alcoholic steatohepatitis.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Aldehydes; Animals; Antioxidants; Body Weight; Deoxyguanosine; Disease Models, Animal; Eriobotrya; Fatty Liver; Liver; Liver Cirrhosis, Experimental; Liver Function Tests; Male; Organ Size; Oxidative Stress; Plant Extracts; Rats; Rats, Wistar; Seeds; Transforming Growth Factor beta

Non-alcoholic fatty liver disease is a common condition that can progress to endstage liver disease. The steatotic liver seems to be particularly susceptible to oxidative stress damage. The aim of this study was to evaluate the redox state in patients with non-alcoholic steatohepatitis (NASH) and its correlation with dietary intake.. Plasma concentrations of 4-hydroxynonenal (4-HNE), 8-hydroxydeoxyguanosine (8-OHdG), reduced and oxidized glutathione (GSH and GSSG), vitamins A and E, total antioxidant status (TAS), glutathione peroxidase (GSH-Px) and reductase (GSH-Red) erythrocyte activities were compared between 43 NASH patients and 33 healthy controls. 4-HNE, GSH-Px, GSH-Red and TAS were evaluated by spectrophotometry, 8-OHdG by ELISA assay, GSH and GSSG by fluorimetric assay and vitamins A and E by high performance liquid chromatography. Dietary habits were also evaluated in these patients.. GSH levels (21.1 +/- 18.3 versus 33.1 +/- 22.2 microM, p = 0.01) and GSH/GSSG ratio (0.9 +/- 0.7 versus 1.5 +/- 0.8, p = 0.01) were lower and TAS (832 +/- 146 versus 630 +/-140 microM, p < 0.001) and vitamin E (47.1 +/- 14.9 versus 34.5 +/- 7.3 microM, p < 0.001) were higher in NASH patients, although there was no difference in GSH-Px and GSH-Red activities, 8-OHdG and 4-HNE levels between groups. After adjusting for total energy consumption, a negative correlation was found with total and saturated fat intake and GSH/GSSG ratio, and a positive correlation with carbohydrates, fiber, monounsaturated fatty acids (MUFA), polyunsaturated fatty acids (PUFA), specifically N-3 PUFA, and vitamins E, C, selenium and folate.. Our data suggest an impaired glutathione metabolism towards an oxidant status in NASH patients, correlating with a higher intake of saturated fat and a lower intake of carbohydrates. Plasmatic concentrations of oxidative stress cellular markers did not translate to hepatic oxidative damage.

Topics: Adult; Aged; Aldehydes; Diet; Dietary Carbohydrates; Dietary Fats; Erythrocytes; Fatty Liver; Female; Glutathione Peroxidase; Glutathione Reductase; Guanosine; Humans; Male; Middle Aged; Oxidative Stress; Vitamin E

The mechanisms of progression from fatty liver to steatohepatitis and cirrhosis are not well elucidated. Mitochondrial dysfunction represents a key factor in the progression of non-alcoholic steatohepatitis (NASH) as mitochondria are the main cellular site of fatty acid oxidation, ATP synthesis and reactive oxygen species (ROS) production.. (1) To evaluate the role of the uncoupling protein 2 in controlling mitochondrial proton leak and ROS production in NASH rats and humans; and (2) to assess the acute liver damage induced by ischaemia-reperfusion in rats with NASH.. Mitochondria were extracted from the livers of NASH humans and rats fed a methionine and choline deficient diet. Proton leak, H(2)O(2) synthesis, reduced glutathione/oxidised glutathione, 4-hydroxy-2-nonenal (HNE)-protein adducts, uncoupling protein-2 (UCP2) expression and ATP homeostasis were evaluated before and after ischaemia-reperfusion injury.. NASH mitochondria exhibited an increased rate of proton leak due to upregulation of UCP2. These results correlated with increased production of mitochondrial hydrogen peroxide and HNE-protein adducts, and decreased hepatic ATP content that was not dependent on mitochondrial ATPase dysfunction. The application of an ischaemia-reperfusion protocol to these livers strongly depleted hepatic ATP stores, significantly increased mitochondrial ROS production and impaired ATPase activity. Livers from patients with NASH exhibited UCP2 over-expression and mitochondrial oxidative stress.. Upregulation of UCP2 in human and rat NASH liver induces mitochondrial uncoupling, lowers the redox pressure on the mitochondrial respiratory chain and acts as a protective mechanism against damage progression but compromises the liver capacity to respond to additional acute energy demands, such as ischaemia-reperfusion. These findings suggest that UCP2-dependent mitochondria uncoupling is an important factor underlying events leading to NASH and cirrhosis.

Topics: Acute Disease; Adenosine Triphosphatases; Adenosine Triphosphate; Adult; Aldehydes; Animals; Disease Progression; Fatty Liver; Female; Humans; Ion Channels; Liver; Male; Membrane Potential, Mitochondrial; Middle Aged; Mitochondria, Liver; Mitochondrial Proteins; Oxidative Stress; Rats; Rats, Wistar; Reactive Oxygen Species; Reperfusion Injury; Uncoupling Protein 2

To evaluate whether chronic therapy with probiotics affects plasma levels of cytokines and oxidative/nitrosative stress parameters, as well as liver damage, in patients with various types of chronic liver disease.. A total of 22 nonalcoholic fatty liver disease (NAFLD) and 20 alcoholic liver cirrhosis (AC) patients were enrolled in the study and compared with 36 HCV-positive patients with chronic hepatitis without (20, CH) or with (16, CC) liver cirrhosis. All patients were treated with the probiotic VSL#3. Routine liver tests, plasma levels of tumor necrosis factor alpha (TNF-alpha), interleukin (IL)-6 and -10, malondialdehyde (MDA), and 4-hydroxynonenal (4-HNE), S-nitrosothiols (S-NO), were evaluated on days -30, 0, 90, and 120.. Treatment with VSL#3 exerted different effects in the various groups of patients: in NAFLD and AC groups, it significantly improved plasma levels of MDA and 4-HNE, whereas cytokines (TNF-alpha, IL-6, and IL-10) improved only in AC patients. No such effects were observed in HCV patients. Routine liver damage tests and plasma S-NO levels were improved at the end of treatment in all groups.. Results of the study suggest that manipulation of intestinal flora should be taken into consideration as possible adjunctive therapy in some types of chronic liver disease.

Topics: Adult; Aldehydes; Analysis of Variance; Chronic Disease; Cytokines; Fatty Liver; Female; Hepatitis C, Chronic; Humans; Liver Diseases, Alcoholic; Liver Function Tests; Male; Malondialdehyde; Middle Aged; Oxidative Stress; Probiotics; S-Nitrosothiols; Statistics, Nonparametric

Oxidative stress contributes to the pathogenesis of chronic hepatitis C. The aim of this study was to assess the peroxidation of n-3 polyunsaturated fatty acids (PUFAs) in the liver and its relation to hepatic steatosis in chronic hepatitis C.. We immunohistochemically detected malondialdehyde (MDA)-, 4-hydroxy-2-nonenal (HNE)-, and 4-hydroxy-2-hexenal (HHE)-protein adducts in liver biopsy specimens from 55 patients with chronic hepatitis C. Cells stained positively for HHE-protein adducts were quantified using computer-based image analysis. Fatty-acid composition was determined, by gas chromatography, for the noncancerous portions of resected livers, with or without steatosis, obtained from two patients with hepatitis C virus-associated hepatocellular carcinoma.. The detection rate of HHE-protein adducts (63.6%) was significantly higher than that of MDA-protein adducts (21.8%; P < 0.001) or HNE-protein adducts (29.1%; P < 0.001). Areas positively stained for HHE-protein adducts (HHE-positive areas) were significantly larger in 18 patients with steatosis (6.2 +/- 3.6%) than in 17 patients without steatosis (3.4 +/- 2.6%; P = 0.01). Resected liver tissue with steatosis showed a larger HHE-positive area (18.6%) and higher ratio of n-6 PUFA content to n-3 PUFA content (3 : 1) than liver tissue without steatosis (7.2%; 2 : 3). On multivariate analysis, the HHE-positive area (odds ratio, 1.55; 95% confidence interval [CI], 1.08-2.23; P = 0.019) was a factor associated with the presence of hepatic steatosis.. HHE-protein adducts, which are a good marker for oxidative stress, are associated with steatosis in chronic hepatitis C.

Topics: Adult; Aged; Aged, 80 and over; Aldehydes; Biomarkers; Biopsy; Chromatography, Gas; Fatty Acids, Omega-3; Fatty Acids, Unsaturated; Fatty Liver; Female; Hepatitis C, Chronic; Humans; Immunohistochemistry; Lipid Peroxidation; Male; Malondialdehyde; Middle Aged; Oxidative Stress; Severity of Illness Index; Triglycerides

The pathogenesis of non-alcoholic steatohepatitis (NASH) is poorly understood. The aim of this study was to examine genetic influences on NASH pathogenesis.. Blood samples from 63 patients with biopsy-proven NASH and 150 healthy controls were analyzed by the polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP). Two functional polymorphisms were studied: the -493 G/T polymorphism in the promoter of microsomal triglyceride transfer protein (MTP) and the 1183 T/C polymorphism in the mitochondrial targeting sequence of manganese superoxide dismutase (MnSOD).. NASH patients had a much higher incidence of the MTP gene G allele (P=0.001) and of the G/G genotype (P=0.002) compared to the controls. Fat occupied more area in liver lobules and the stage of NASH was advanced in patients with the G/G-genotype than in patients with G/T-genotype (P=0.04). NASH patients also had a higher incidence of the MnSOD T/T genotype (P=0.016).. The G allele in the MTP promoter leads to decreased MTP transcription, less export of triglyceride from hepatocytes, and greater intracellular triglyceride accumulation. The T allele in MnSOD mitochondrial targeting sequence leads to less transport of MnSOD to the mitochondria. Therefore, functional polymorphisms in MTP and MnSOD may be involved in determining susceptibility of NASH.

Topics: Adult; Aldehydes; Alleles; Base Sequence; Carrier Proteins; Case-Control Studies; DNA; Fatty Liver; Female; Gene Frequency; Hepatitis, Chronic; Humans; Male; Middle Aged; Polymorphism, Genetic; Polymorphism, Single Nucleotide; Superoxide Dismutase; Syndrome

Fatty liver caused by ethanol decreases survival after liver transplantation in rats. This study investigated if antioxidant polyphenols from Camellia sinenesis (green tea) prevent failure of fatty grafts from ethanol-treated rats. Donor rats were given ethanol intragastrically (6 g/kg). After 20 h, livers were explanted and stored in University of Wisconsin solution for 24 h. Prior to implantation, the explanted grafts were rinsed with lactated Ringer's solution containing 0 to 60 microg/ml polyphenols. Alanine aminotransferase (ALT) release after liver transplantation was 4.5-fold higher in recipients receiving ethanol-induced fatty grafts than in those receiving normal grafts. Liver grafts from ethanol-treated donors also developed severe focal necrosis. Graft survival was 11% in the ethanol group versus 88% for normal grafts. Polyphenol treatment at 60 microg/ml blunted ALT release by 66%, decreased necrotic areas by 84%, and increased survival to 75%. Ethanol increased alpha-(4-pyridyl-1-oxide)-N-tert.-butylnitrone free radical adducts in bile by 2.5-fold, as measured by electron spin resonance spectroscopy, and caused accumulation of 4-hydroxynonenal in liver sections, effects blunted by polyphenols. Epicatechin gallate, a major polyphenol from C. sinenesis, also decreased enzyme release, minimized pathological changes, and decreased free radical adduct formation. In conclusion, polyphenols scavenged free radicals in ethanol-induced fatty livers and decreased injury after liver transplantation.

Topics: Alanine Transaminase; Aldehydes; Animals; Antioxidants; Bile; Camellia; Catechin; Central Nervous System Depressants; Electron Spin Resonance Spectroscopy; Ethanol; Fatty Liver; Female; Flavonoids; Free Radical Scavengers; Free Radicals; Graft Survival; Liver Transplantation; Necrosis; Phenols; Polyphenols; Rats; Rats, Sprague-Dawley

Although oxidative stress is an important candidate in the pathogenesis of non-alcoholic fatty liver disease (NAFLD), the localization and pathological significance of oxidative stress-induced cellular damage in NAFLD remains unclear.. Hepatic expression of 4-hydroxy-2'-nonenal (HNE) and 8-hydroxydeoxyguanosine (8-OHdG), as reliable markers of lipid peroxidation and oxidative DNA damage, respectively, was immunohistochemically investigated in NAFLD and the results were compared with histological findings.. While no HNE adducts were observed in control livers, they were frequently detected in NAFLD. In NASH, the localization of the adducts was in the cytoplasm of sinusoidal cells and hepatocytes with a predominance in zone 3. The grade of necro-inflammation as well as the stage of fibrosis significantly correlated with the HNE index. Regarding 8-OHdG, although no 8-OHdG expression was observed in normal liver and only a few in fatty liver, 11 of 17 cases (64.7%) with NASH exhibited nuclear expression of 8-OHdG in hepatocytes and sinusoidal cells in areas of active inflammation. The 8-OHdG index significantly correlated with the grade of necro-inflammation.. Oxidative cellular damage occurs frequently in livers with NAFLD and may be associated with some clinico-pathological features of NAFLD including liver fibrosis and possibly, hepatocarcinogenesis.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Aged; Aldehydes; Deoxyguanosine; DNA Damage; Fatty Liver; Female; Humans; Immunohistochemistry; Lipid Peroxidation; Liver; Male; Middle Aged; Oxidative Stress

Liver proteins form adducts with acetaldehyde and are modified by products of lipid peroxidation in alcohol-fed animals. It has been hypothesized that the formation of these modified liver proteins may contribute to liver injury in alcoholic liver disease. The present work was performed to determine the extent of protein modification in rats with experimental alcoholic liver disease. Rats were fed ethanol intragastrically with medium chain triglycerides (MCTs), palm oil, corn oil, or fish oil. The group fed MCTs and ethanol showed no liver injury, rats fed palm oil and ethanol showed only fatty liver, rats fed corn oil and ethanol showed fatty liver with moderate necrosis and inflammation, and rats fed fish oil and ethanol showed fatty liver with severe necrosis and inflammation. Antibodies were raised by using keyhole limpet hemocyanin modified in vitro by 4-hydroxynonenal (4-HNE) or acetaldehyde as immunogens. When liver extracts were examined by Western blot analysis, the intensities of the acetaldehyde-modified protein band (37 kd) in the alcohol-fed animals were significantly different among the ethanol-treated groups and correlated with plasma acetaldehyde concentrations. It was strongest in rats fed fish oil and ethanol, followed by rats fed palm oil and ethanol and rats fed corn oil and ethanol, whereas rats fed MCTs and ethanol showed the weakest intensity. The 37-kd protein-adetaldehyde adduct was located mainly in the pericentral region of the liver. No acetaldehyde adduct was detected in the control rats that were pair-fed with isocaloric amounts of dextrose. Western blot analysis using the anti-4-HNE antibody showed four distinctive bands (48, 45, 40, and 38 kd) in the liver extracts of alcohol-fed rats. Control animals showed only a weak 38-kd band. Although the intensities of the 48-, 40-, and 38-kd bands were similar among the different ethanol-treated groups, the intensity of the 45-kd band decreased from MCTs and ethanol > palm oil and ethanol > or = corn oil and ethanol > fish oil and ethanol. The data indicate that the degree of liver protein modification by acetaldehyde correlates well with the severity of liver injury in ethanol-fed rats, whereas modification by the lipid peroxidation product 4-HNE shows no correlation with the severity of liver injury.

Topics: Acetaldehyde; Aldehydes; Animals; Antibodies; Corn Oil; Dietary Fats; Fatty Liver; Fish Oils; Humans; Inflammation; Liver; Liver Diseases, Alcoholic; Male; Necrosis; Palm Oil; Plant Oils; Proteins; Rats; Rats, Wistar; Serum Albumin