2C). Alcohol is also known to decrease peroxisomal lipid metabolism23 and we found decreased expression of acyl-coenzyme A oxidase 1, palmitoyl (Acox1) in strains with severe fatty liver (Fig. 2D). Finally, the fat-derived hormone adiponectin alleviates alcoholic fatty liver disease in mice24 and liver adiponectin receptor 2 (Adipor2) expression was decreased by alcohol treatment in mice,25 an effect that was not observed in alcoholic liver injury-resistant strains (Fig. 2E). Mice of different strains

received the same dose of alcohol under identical experimental conditions and the daily urine concentrations of alcohol were measured (Fig. 1C). In all mice a characteristic find more cyclic fluctuation in urine alcohol concentration26 was observed. Importantly, peak urine alcohol concentration (in treated animals) was not significantly correlated with the severity of steatohepatitis or other markers of liver injury (see Supporting Table 2 for the correlation analysis matrix). Chronic alcohol-induced liver injury has been associated with www.selleckchem.com/products/BKM-120.html ER stress and alterations in lipid synthesis pathways.27 In addition, it has been shown that unresolved ER stress may also

lead to steatosis through inhibition of lipid oxidation, instead of de novo lipogenesis, as down-regulation of sterol regulatory element binding transcription factor 1 (Srebf1) and CCAAT/enhancer-binding protein alpha

(Cebpa), key transcription factors involved in fatty acid metabolism, were observed.28 In some strains that exhibited the greatest degree of alcohol-induced liver injury, a concordant induction of ER stress factors Grp78 (Fig. 3A) and Chop (Fig. 3B,C), and dysregulation of Cebpa (Fig. 3D) and Srebf1 (Fig. 3E), as well as a decrease activated cleaved Srebp1 (Fig. 3F), was observed. Oxidative stress and lipid peroxidation are well-established hallmarks of alcohol-induced liver injury.29 Hepatic GSH depletion after chronic alcohol consumption was shown both in experimental animals and in humans.30 We evaluated the content of GSH and GSSG in livers of alcohol- and HFD-fed mice (Fig. 4). GSH depletion was observed in most of the strains (Fig. L-gulonolactone oxidase 4A), and the level of GSH was significantly inversely correlated with the severity of liver injury only when both control and alcohol-fed groups were considered. Although in most strains a modest increase in GSSG was observed (Fig. 4B), the effect was not significant and no correlation with liver injury was observed. Reduction in the GSH/GSSG ratio (Fig. 4C) across the panel of strains followed closely the changes observed with GSH. Alterations of methionine metabolism have been suggested to play an important role in the pathogenesis of alcoholic liver disease.