Alcoholic Steatosis Research Articles

Other complications and associated conditions with diabetes in children and adolescents

aChildren’s Hospital auf der Bult, Hannover, Germany; bthe Children’s Hospital at Westmead, NSW, Australia; cUniversity of Helsinki, Finland; dMedical University Vienna, Austria; eUniversity of Genova, Italy; fUniversitat Ulm, Uni West, Germany; gUniversity of Sydney, Australia Corresponding author: Prof. Dr. med. Olga Kordonouri Diabetes Center for Children and Adolescents Children’s Hospital auf der Bult Hannover, Germany Tel: +49 511/8115-3340; fax: +49 511/8115-3334; e-mail: kordonouri@hka.de

Protective effects of saponins from the root of Platycodon grandiflorum against fatty liver in chronic ethanol feeding via the activation of AMP-dependent protein kinase

Fatty liver and steatosis induced by alcohol is the earliest and most common response of the liver to alcohol and may be a precursor of more severe forms of liver injury. However, the mechanism of liver injury and deposition of fatty liver due to alcohol is complex. The protective effects of saponins from the root of Platycodon grandiflorum (Changkil saponins: CKS) against ethanol-induced liver injury in an enteral alcohol feeding model was investigated. Male Sprague–Dawley rats were given control diets or ethanol-containing diets enterally for 4 weeks. Treatment with CKS for 2 weeks significantly prevented the alcohol-induced increase in serum alanine aminotransferase and aspartate aminotransferase activities or decrease in serum albumin levels. Alcohol elevated the hepatic triglyceride content and induced cytochrome P450 2E1 (CYP2E1) expression. CKS treatment reduced CYP2E1 expression and hepatic triglyceride accumulation and prevented alcoholic liver steatosis. Chronic alcohol feeding decreased AMP-activated protein kinase-alpha (AMPKα) phosphorylation, which was restored by CKS treatment. Recovery of AMPKα phosphorylation by CKS was also followed by an increase in acetyl-CoA carboxylase phosphorylation. Our study suggests that CKS is a promising agent for preventing or treating human alcoholic fatty liver disease.

L’alcool et le foie

The risk of developing alcohol-induced liver injury occurs above a risk threshold around 25-30g/day. A dose-dependent relationship between alcohol intake and the risk of developing alcohol-induced liver injury is observed in alcoholic subjects with a daily consumption above this threshold. Cirrhosis is the first cause of death related to alcohol. Cirrhosis occurs more frequently in heavy drinkers disclosing alcoholic hepatitis or steatosis. Excess weight is a risk factor for alcoholic liver disease. The role of alcohol in mouth, oropharynx and oesophageal cancers is clearly established. The evidence for the role of alcohol in breast cancer has become clear. Corticosteroids improved the short-term survival of patients with severe alcoholic hepatitis. The Lille model identifies patients who will not benefit from corticosteroids. The benefit of liver transplantation is restricted to alcoholic patients with severe cirrhosis. Only abstainers are considered as candidates for liver transplantation. The recent development of non invasive methods opens up new perspectives for the screening of cirrhosis in subjects with heavy drinking.

The increase in plasma PAI-1 associated with insulin resistance may be mediated by the presence of hepatic steatosis

Objective Recent evidence suggests that plasminogen-activator inhibitor-1 (PAI-1) is abundantly produced by the fatty liver, but it is unclear whether hepatic steatosis (HS) can mediate the increase in plasma PAI-1 induced by insulin resistance/compensatory hyperinsulinemia (IR/CH). Methods and results To address this issue, we cross-sectionally evaluated IR/CH as area under the curve of plasma insulin (AUC-PI) concentrations during OGTT, metabolic profile, and ultrasound degree of HS in 235 healthy volunteers (132 M, age: 60 ± 7 years) with normal transaminase concentrations. Circulating PAI-1 was increased in subjects with classical features of IR/CH (overweight, high fasting and post-OGTT insulin and glucose, high triglycerides (TG), and low HDL-cholesterol), and significantly correlated to prevalence and degree of HS, but not to alcohol intake. In a multivariate model, AUC-PI, TG and degree of HS were independent predictors of plasma PAI-1 ( R 2 = 0.32). However, AUC-PI was significantly correlated to PAI-1 only in subjects with HS, suggesting an interaction between AUC-PI and HS. In addition, in the presence of HS and IR/CH, PAI-1 concentrations were increased to a similar extent both in heavy and moderate drinkers, suggesting that metabolic and alcoholic steatosis have a similar effect on the relationship between IR/CH and PAI-1. Conclusion These results support the hypothesis that HS has a major impact on the relationship between IR/CH and plasma PAI-1 concentrations, and this effect seems to be unaffected by the etiology of the HS.

Zinc Supplementation Reverses Alcohol-Induced Steatosis in Mice Through Reactivating Hepatocyte Nuclear Factor-4α and Peroxisome Proliferator-Activated Receptor-α†

Alcoholic steatosis is a fundamental metabolic disorder in the progression of alcoholic liver disease. Zinc deficiency is one of the most consistently observed biochemical/nutritional manifestations of alcoholic liver disease. The purpose of this study is to determine whether dietary zinc supplementation to mice previously exposed to alcohol could reverse alcoholic steatosis. Male 129S mice were pair-fed an alcohol or isocaloric maltose dextrin liquid diet for 16 weeks with or without dietary zinc supplementation for the last 4 weeks. Zinc supplementation significantly attenuated alcohol-mediated increases in hepatic triglyceride, cholesterol, and free fatty acids in association with accelerated hepatic fatty acid oxidation and very low density lipoproteins (VLDL) secretion. Hepatic genes related to fatty acid oxidation and VLDL secretion were up-regulated by zinc supplementation, which was accompanied by restoring activity of hepatocyte nuclear factor-4alpha (HNF-4alpha) and peroxisome proliferators activated receptor-alpha (PPAR-alpha). Zinc supplementation enhanced alcohol metabolism and attenuated oxidative stress and liver injury. Zinc supplementation also normalized alcohol-mediated increases in plasma triglycerides and partially reversed decrease in gonadal adipose depot mass. Studies in HepG2 cells showed that zinc deprivation significantly suppressed the DNA-binding activities of HNF-4alpha and PPAR-alpha, and reduced HNF-4alpha and PPAR-alpha target proteins. Consequently, zinc deprivation caused cellular accumulation of lipid droplets, triglycerides and free fatty acids in the HepG2 cells. Zinc supplementation reverses alcoholic steatosis, and reactivation of HNF-4alpha and PPAR-alpha by increasing zinc availability and inhibiting oxidative stress are potential mechanisms underlying these beneficial effects of zinc on hepatic lipid homeostasis.

Predictive Factors for Pure Steatosis in Alcoholic Patients

Bearing in mind the mechanisms involved in nonalcoholic fatty liver disease, this study aims to verify whether metabolic syndrome or its various individual components are independent predictive factors for steatosis > or =10% in alcoholic patients. This study included 281 consecutive alcoholic patients with abnormal liver tests and either normal liver histology or steatosis <10% (n = 119) or steatosis > or =10% (n = 162). Logistic regression analysis was used to study the relationship between metabolic syndrome components and various risk factors and the presence of steatosis > or =10%. We assessed apolipoprotein A1 (ApoA-1) levels, a major protein component of plasma high-density lipoprotein (HDL), rather than HDL-cholesterol levels. Plasma ApoA-1 levels (p < 0.01), body mass index (BMI) (p < 0.01), and waist circumference (p < 0.05) were significantly higher in patients with steatosis > or =10% than in patients with normal liver histology or steatosis <10%. A higher percentage of patients with steatosis > or =10% had high blood pressure (p = 0.003) than patients with normal liver histology or steatosis <10%. In the logistic regression, ApoA-1 [odds ratio (OR) = 1.57 (1.10-2.22)], BMI [OR = 1.10 (1.01-1.23)], and high blood pressure [OR = 1.84 (1.10-3.06)] were positively and independently correlated with the presence of steatosis > or =10%. In the multivariate regression high blood pressure was independently and positively correlated with steatosis score (r = 0.55 +/- 0.26; p < 0.05). On the other hand, when the presence of high blood pressure was the dependent variable, the presence of steatosis > or =10% positively and independently correlated with it [OR = 1.82 (1.05-3.15)]. In alcoholic patients without fibrosis, ApoA-1, BMI, and high blood pressure on the next morning after the admission were predictive of steatosis > or =10%. High blood pressure was the only metabolic syndrome component associated with the presence of alcoholic steatosis >/=10% and was not correlated with other metabolic syndrome components. These findings suggest that steatosis mechanisms are different in alcoholic and nonalcoholic fatty liver.

ALCOHOL AND HEPATIC STEATOSIS

Alcohol and Hepatic Steatosis Get access Nutrition Reviews, Volume 25, Issue 3, March 1967, Pages 84–86, https://doi.org/10.1111/j.1753-4887.1967.tb05582.x Published: 01 March 1967

Metabolic Syndrome (MetS) and Nonalcoholic Steatohepatitis (NASH): Study of biochemical markers Free Fatty Acid (FFA), Total Antioxidant Status (TAOS), Adiponectin, Transforming Growth Factor (TGF-beta1), in occurence of NASH

BACKGROUND: The prevalence of metabolic syndrome (MetS) in USA and Makassar are 22% and 23.7%. The prevalence of Non Alcoholic Steatosis Hepatosis (NASH) in MetS has not been reported. Study in Non-alcoholic Fatty Liver Disease (NAFLD) is 25–90 % in obesity patients. In NASH, there is accumulation of lipid in hepatocyte (raised free fatty acid level), raised stress oxidative (decreased total antioxidant status), raised of inflammation process (decreased adiponectin) and hepatic fibrotic process (raised TGF β1). The aim of this study is to investigate the correlation of free fatty acid, total antioxidant status, adiponectin and TGF-β1 with the occurrence of NASH.METHODS: This was a case control study in man aged ≥30 years old. Metabolic syndrome (MetS) was defined by IDF categories. NASH was defined as fatty liver plus raised type IV collagen level ≥140 ng/ml and Alanine Transferase (ALT) level 1.5x upper normal limit.RESULT: The samples consisted of 8 MetS subjects, 11 MetS subjects with fatty liver and 2 MetS subjects with suspect NASH. Low level of adiponectin and high level free fatty acid led to progression from Fatty Liver (FL) to NASH. Level of total antioxidant and Level of TGF-β1 were relatively steady in NASH.CONCLUSION: The level of Free Fatty acid in subjects with MetS-FL was higher than in subjects with MetS, but was lower than in subjects with MetS-NASH. No difference in total antioxidants status level was observed among all groups. Level of adiponectin decreased in subjects with MetS-FL and MetS-NASH compared with subjects with MetS only. The level of TGF-β1 increased in subjects with MetS-FL more than in subjects with MetS only, and was steady low in subjects with MetS-NASH.KEYWORDS: metabolic syndrome, NASH, free fatty acid, total antioxidant status, adiponectin, transforming growth factor β1

Betaine administration corrects ethanol-induced defective VLDL secretion

Our previous studies, demonstrating ethanol-induced alterations in phosphatidylcholine (PC) synthesis via the phosphatidylethanolamine methyltransferase (PEMT) pathway, implicated a defect in very low-density lipoprotein (VLDL) secretion in the pathogenesis of hepatic steatosis. The objective of this study was to determine whether VLDL secretion was reduced by chronic ethanol consumption and whether betaine supplementation, that restores PEMT activity and prevents the development of alcoholic steatosis, could normalize VLDL secretion. The VLDL secretion in rats fed with control, ethanol and the betaine supplemented diets was determined using Triton WR-1339 to inhibit plasma VLDL metabolism. We observed reduced VLDL production rates in chronic alcohol-fed rats compared to control animals. Supplementation of betaine in the ethanol diet increased VLDL production rate to values significantly higher than those observed in the control diet-fed rats. To conclude, chronic ethanol consumption impairs PC generation via the PEMT pathway resulting in diminished VLDL secretion which contributes to the development of hepatic steatosis. By increasing PEMT-mediated PC generation, betaine results in increased fat export from the liver and attenuates the development of alcoholic fatty liver.

Liver Proteome Analysis in a Rodent Model of Alcoholic Steatosis

Alcoholic steatosis (AS) is the initial pathology associated with early stage alcoholic liver disease (ALD) and is characterized by the accumulation of fat in the liver. AS is considered clinically benign because it is reversible, and the progression of AS to alcoholic steatohepatitis (ASH) is a key step in the development of ALD. A two-dimensional gel electrophoresis (2DE)-mass spectrometry (MS) proteomic approach was used to investigate the protein expression pattern underlying AS, as the first step toward determining liver tissue biomarkers for early stage ALD. Several proteins involved in fatty acid and amino acid metabolism were up-regulated in 3- and 6-week ethanol-fed rats relative to isocaloric controls, which suggest a higher energy demand upon chronic exposure to ethanol. In addition, the expression of two proteins associated with alcohol-induced oxidative stress, peroxiredoxin 6 (PRDX6) and aldehyde dehydrogenase 2 (ALDH2), was down-regulated in ethanol fed rats, and suggests an increase in reactive oxygen species and oxidative stress. To investigate if irreversible protein modification arising from oxidative stress during AS impacts protein levels, the extent of carbonylated proteins in the ethanol and isocaloric groups was identified using mass spectrometry. The detection of modified proteins involved in antioxidant functions further supports the notion that oxidative modification of these proteins leads to protein turnover during AS. In addition, the carbonylation of betaine-homocysteine S-methyltransferase, a protein implicated in fatty liver development, in 3-week and 6-week ethanol exposed samples suggests that this protein could be a marker for early stage AS.

Honokiol reverses alcoholic fatty liver by inhibiting the maturation of sterol regulatory element binding protein-1c and the expression of its downstream lipogenesis genes

Ethanol induces hepatic steatosis via a complex mechanism that is not well understood. Among the variety of molecules that have been proposed to participate in this mechanism, the sterol regulatory element (SRE)-binding proteins (SREBPs) have been identified as attractive targets for therapeutic intervention. In the present study, we evaluated the effects of honokiol on alcoholic steatosis and investigated its possible effect on the inhibition of SREBP-1c maturation. In in vitro studies, H4IIEC3 rat hepatoma cells developed increased lipid droplets when exposed to ethanol, but co-treatment with honokiol reversed this effect. Honokiol inhibited the maturation of SREBP-1c and its translocation to the nucleus, the binding of nSREBP-1c to SRE or SRE-related sequences of its lipogenic target genes, and the expression of genes for fatty acid synthesis. In contrast, magnolol, a structural isomer of honokiol, had no effect on nSREBP-1c levels. Male Wistar rats fed with a standard Lieber–DeCarli ethanol diet for 4 weeks exhibited increased hepatic triglyceride and decreased hepatic glutathione levels, with concomitantly increased serum alanine aminotransferase and TNF-α levels. Daily administration of honokiol (10 mg/kg body weight) by gavage during the final 2 weeks of ethanol treatment completely reversed these effects on hepatotoxicity markers, including hepatic triglyceride, hepatic glutathione, and serum TNF-α, with efficacious abrogation of fat accumulation in the liver. Inhibition of SREBP-1c protein maturation and of the expression of Srebf1c and its target genes for hepatic lipogenesis were also observed in vivo. A chromatin immunoprecipitation assay demonstrated inhibition of specific binding of SREBP-1c to the Fas promoter by honokiol in vivo. These results demonstrate that honokiol has the potential to ameliorate alcoholic steatosis by blocking fatty acid synthesis regulated by SREBP-1c.

Analysis of hepatic gene expression during fatty liver change due to chronic ethanol administration in mice

Chronic consumption of ethanol can cause cumulative liver damage that can ultimately lead to cirrhosis. To explore the mechanisms of alcoholic steatosis, we investigated the global intrahepatic gene expression profiles of livers from mice administered alcohol. Ethanol was administered by feeding the standard Lieber–DeCarli diet, of which 36% (high dose) and 3.6% (low dose) of the total calories were supplied from ethanol for 1, 2, or 4 weeks. Histopathological evaluation of the liver samples revealed fatty changes and punctate necrosis in the high-dose group and ballooning degeneration in the low-dose group. In total, 292 genes were identified as ethanol responsive, and several of these differed significantly in expression compared to those of control mice (two-way ANOVA; p < 0.05). Specifically, the expression levels of genes involved in hepatic lipid transport and metabolism were examined. An overall net increase in gene expression was observed for genes involved in (i) glucose transport and glycolysis, (ii) fatty acid influx and de novo synthesis, (iii) fatty acid esterification to triglycerides, and (iv) cholesterol transport, de novo cholesterol synthesis, and bile acid synthesis. Collectively, these data provide useful information concerning the global gene expression changes that occur due to alcohol intake and provide important insights into the comprehensive mechanisms of chronic alcoholic steatosis.

Saponins isolated from the root of Platycodon grandiflorum protect against acute ethanol-induced hepatotoxicity in mice

The protective effects of saponins isolated from the root of Platycodon grandiflorum (Changkil saponins: CKS) against alcoholic steatosis in liver injury induced by acute ethanol administration were investigated. Pretreatment with CKS prior to ethanol administration significantly prevented the increases in serum alanine aminotransferase activity, hepatic TNF-α level, hepatic lipid peroxidation and hepatic triglyceride level. CKS prevented ethanol-induced steatosis and necrosis, as indicated by liver histopathological studies. Additionally, CKS protected against ethanol-induced depletion of hepatic glutathione levels. CYP2E1 has been suggested as a major contributor to ethanol-induced oxidative stress and liver injury. The concurrent administration of CKS efficaciously abrogated the CYP2E1 induction and CYP2E1-dependents hydroxylation of aniline as compared to the individual treatment at higher doses. These findings suggest that CKS may prevent ethanol-induced acute liver injury, possibly through its ability to block CYP2El-mediated ethanol bioactivation and its free radical scavenging effects.

Down-regulation of liver Gal β1, 4GlcNAc α2, 6-sialyltransferase gene by ethanol significantly correlates with alcoholic steatosis in humans

Hepatic steatosis and steatohepatitis are frequent results of long-term ethanol exposure. We have previously demonstrated that long-term ethanol down-regulates Gal βl, 4GlcNAc α2, 6-sialyltransferase (ST6Gal1), leading to defective glycosylation of a number of proteins including apolipoprotein (apo) E and apo J and the appearance of asialoconjugates in the blood of continuously alcohol-fed animals as well as in human alcoholics. In the current study, we have explored the possibility of whether ethanol-induced down-regulation of ST6Gal1 could contribute toward alcoholic steatosis in human alcoholics presumably because of impaired lipid and lipoprotein transport caused by this down-regulation. Real-time quantitative polymerase chain reaction analyses of liver samples from nondrinkers, moderate drinkers, and heavy drinkers as well as from subjects with and without alcoholic liver disease revealed direct evidence that the down-regulation of ST6Gal1 may be due to ethanol per se. The ST6Gal1 messenger RNA level was reduced by as much as 70% in moderate and heavy drinkers as well as in patients with alcoholic liver disease, but was not changed in subjects with liver disease due to causes other than alcohol exposure. Biochemical and histopathologic analysis demonstrated that the liver total cholesterol was increased by more than 30% ( P < .05) and 75% ( P < .01), respectively, in moderate and heavy drinkers compared with nondrinkers, with even more dramatic changes in triglyceride levels. Significantly, there was a strong inverse correlation between ST6Gal1 messenger RNA level and liver lipid deposit (F = 8.68, P < .001) by statistical analysis. Thus, it is suggested that alcohol-mediated down-regulation of hepatic ST6Gal1 gene leads to defective glycosylation of lipid-carrying apolipoproteins such as apo E and apo J, resulting in defective intracellular lipid and lipoprotein transport, which in turn may contribute to alcoholic steatosis.

Resveratrol alleviates alcoholic fatty liver in mice

Alcoholic fatty liver is associated with inhibition of sirtuin 1 (SIRT1) and AMP-activated kinase (AMPK), two critical signaling molecules regulating the pathways of hepatic lipid metabolism in animals. Resveratrol, a dietary polyphenol, has been identified as a potent activator for both SIRT1 and AMPK. In the present study, we have carried out in vivo animal experiments that test the ability of resveratrol to reverse the inhibitory effects of chronic ethanol feeding on hepatic SIRT1-AMPK signaling system and to prevent the development of alcoholic liver steatosis. Resveratrol treatment increased SIRT1 expression levels and stimulated AMPK activity in livers of ethanol-fed mice. The resveratrol-mediated increase in activities of SIRT1 and AMPK was associated with suppression of sterol regulatory element binding protein 1 (SREBP-1) and activation of peroxisome proliferator-activated receptor gamma coactivator alpha (PGC-1alpha). In parallel, in ethanol-fed mice, resveratrol administration markedly increased circulating adiponectin levels and enhanced mRNA expression of hepatic adiponectin receptors (AdipoR1/R2). In conclusion, resveratrol treatment led to reduced lipid synthesis and increased rates of fatty acid oxidation and prevented alcoholic liver steatosis. The protective action of resveratrol is in whole or in part mediated through the upregulation of a SIRT1-AMPK signaling system in the livers of ethanol-fed mice. Our study suggests that resveratrol may serve as a promising agent for preventing or treating human alcoholic fatty liver disease.

Adiponectin and alcoholic fatty liver disease

Worldwide, one of the most prevalent forms of chronic disease is alcoholic fatty liver, which may progress to more severe forms of liver injury including steatohepatitis, fibrosis, and cirrhosis. The molecular mechanisms by which ethanol consumption causes accumulation of hepatic lipid are multiple and complex. Chronic ethanol exposure is thought to cause enhanced hepatic lipogenesis and impaired fatty acid oxidation by inhibiting key hepatic transcriptional regulators such as AMP-activated kinase (AMPK), sirtuin 1 (SIRT1), PPAR-gamma coactivator alpha (PGC-1alpha), peroxisome proliferator-activated receptor alpha (PPARalpha), and sterol regulatory element-binding protein 1 (SREBP-1). Adiponectin is an adipose-derived hormone with a variety of beneficial biological functions. Increasing evidence suggests that altered adiponectin production in adipose tissue and impaired expression of hepatic adiponectin receptors (AdipoRs) are associated with the development of alcoholic liver steatosis in several rodent models. More importantly, studies have demonstrated a protective role of adiponectin against alcoholic liver steatosis. The hepato-protective effect of adiponectin is largely mediated by the coordination of multiple signaling pathways in the liver, leading to enhanced fat oxidation, reduced lipid synthesis and prevention of hepatic steatosis. This review begins with an assessment of the current understanding of the role of adiponectin and its receptors in the regulation of lipid homeostasis in liver, with emphasis on their relationship to the development of alcoholic liver steatosis. Following sections will review hepatic signaling molecules involved in the protective actions of adiponectin against alcoholic fatty liver and summarize the current knowledge of regulatory mechanisms of adiponectin expression and secretion in response to chronic ethanol exposure. We will conclude with a discussion of potential strategies for treating human alcoholic fatty liver disease (AFLD), including nutritional and pharmacological modulation of adiponectin and its receptors.

Alcohol—intoxicating roadblocks and bottlenecks in hepatic protein and lipid metabolism

with over 60% of the population consuming alcohol during the past year, and 32% admitting to engaging in alcohol binging episodes, alcohol abuse continues to be a comorbid condition for several diseases, but in particular for liver disease. Liver disease is one of the most salient pathophysiological

M1760 Bifidobacteria Attenuate the Development of Non-Alcoholic Fatty Liver in Obese Mice

Our laboratory has previously shown that ethanol causes defects in methionine metabolism which result in higher levels of two toxic metabolites, homocysteine and S-adenosylhomocysteine (SAH). These metabolites, in turn, contribute to the development of characteristic features of alcoholic liver injury via impairments in crucial transmethylation reactions. We have further reported that dietary betaine supplementation alleviates ethanol-induced changes in intracellular SAH levels to mitigate steatosis, apoptosis and damaged protein accumulation, thereby preventing the progression to fibrosis and cirrhosis. We have data that shows that this protective effect of betaine is due to its ability to donate methyl groups to homocysteine via reactions catalyzed by the betaine homocysteine methyltransferase (BHMT) enzyme to generate methionine. In our search for alternates to betaine, we found that sulphur-containing analogs of betaine called thetins are alternative methyl-donor substrates of BHMT. The purpose of this study therefore was to compare the efficacy of betaine and one such analog, dimethylacetothetin (DMAT) in preventing alcoholic liver injury. The chronic ethanol feeding model which shows characteristic features of alcoholic liver injury after 4-5 weeks of ethanol exposure was utilized. Male Wistar rats (180-200 g BW) were fed the control or ethanol diet. Additional groups were fed the ethanol diet-supplemented with 1% betaine or 0.5% DMAT. All rats were sacrificed at the end of 4-5 weeks of feeding. Blood was collected and livers were excised and freeze-clamped and stored at -70°C until analyzed. We observed that while both compounds, betaine and DMAT, were effective in reducing fat accumulation in the liver, DMAT was more effective than betaine in preventing alcoholic steatosis (p < 0.05). Betaine supplemented as 1% in ethanol diet reduced the elevated liver triglycerides by ~50% (p < 0.05). However, DMAT at only a 0.5% supplementation reduced the liver triglycerides to levels seen in the control diet-fed animals. The blood ethanol levels were similar in ethanol-fed rats as compared to the betaine or DMAT-supplemented ethanol diet fed groups. We further showed that DMAT is a an exceptionally good substrate for BHMT, is 20 times more effective than betaine in remethylating homocysteine (p < 0.05) and also more efficacious in preventing methionine-induced hyperhomocysteinemia (p < 0.05). To conclude, DMAT should be considered as an alternative therapeutic agent to betaine for the treatment of alcoholic and non-alcoholic liver disease.

Alcohol and lipid metabolism

Many new mechanisms for alcoholic steatosis have been suggested by work reported in the last five years. These include alterations of transcriptional controls of lipid metabolism, better understanding of the effects of abnormal methionine metabolism on the endoplasmic reticulum stress response, unraveling of the basis for sensitization of the Kupffer cell to lipopolysaccharide, a better understanding of the role of cytokines and adipokines in alcoholic liver disease, and implication of the innate immune and complement systems in responses to alcohol. Much of this work has been facilitated by work with knockout mice. Undoubtedly, there are interrelationships among these various pathogenic mechanisms that ultimately will provide a more cohesive picture of how heavy alcohol use deranges hepatic lipid metabolism.

Efficacious treatment of alcoholic steatosis by a pharmaceutical composition comprising metadoxine and garlic oil

Alcoholic steatosis is the earliest and common response to heavy alcohol intake, and may precede severe forms of liver injury. As an effort to develop an efficacious pharmaceutical composition, this study evaluated the effects of metadoxine, garlic oil or their combination on alcoholic steatosis. Feeding rats an alcohol‐containing diet for 4 weeks increased hepatic triglyceride content with CYP2E1 induction. Concurrent administration of metadoxine and garlic oil (MG, 1:1 w/w ratio) to rats synergistically abrogated both fat accumulation and CYP2E1 induction compared to the individual treatment. Histopathology confirmed the ability of MG combination to inhibit lipid accumulation. Blood biochemistry verified improvement of liver function in MG‐treated rats. Alcohol administration resulted in decreases in the AMPKα and ΑCC phosphorylations, which was restored by MG treatments. Hepatic fatty acid synthase (FAS) expression was decreased after alcohol consumption, which correlated with a decrease in AMPK activity and a commensurate increase in lipid content. Combined MG treatments allowed FAS expression restored. These results demonstrate that a pharmaceutical composition comprising MG effectively treats alcoholic steatosis, which may be associated with CYP2E1 repression and recovery of AMPK activity, promising pharmaceutical therapy for alcoholic steatosis.Supported by a contract fund from the Seoul R&amp;BD Program (2005–2010).