Thus, dysregulation of one-carbon metabolism genes may lead not only to a more severe alcoholic liver injury, but also to hyperhomocysteinemia in sensitive strains. Several aspects of our study deserve further comment. First, we examined only one timepoint and the changes we observed may not be reflective of what occurred earlier in response to alcohol, nor what might occur later, as the complex adaptive, metabolic, and injury pathways adjust or maladjust. Second, although some of our findings demonstrate striking differences between alcohol and control but no correlation with disease severity, this should not

be taken as evidence that these changes are unimportant; the results simply suggest that these are not determinants of strain differences. Nevertheless, they could reflect important universal effects of alcohol that are Napabucasin prerequisites for the additional genetic responses to influence disease severity. For example, hepatic levels of GSH, SAM/SAH, and homocysteine show marked differences

across most of the alcohol versus pair-fed strains. Third, we have not measured protein expression and enzyme activity of most of the various apparently dysregulated gene transcripts, so our findings do not take into consideration translational or posttranslational effects on these systems of VX-809 cost lipid and one-carbon metabolism and such effects could also be genetically determined. Nevertheless, notwithstanding the limitations, the findings of our initial approach indicate that genetic strain differences in liver injury and steatosis are striking and independent of alcohol exposure and the most severely affected strains exhibit major differences in the expression selleck chemicals of ER stress markers and genes of one-carbon metabolism. The significant correlation across species in plasma homocysteine and alcohol-induced steatohepatitis stands out as a marker of dysregulated one-carbon metabolism and confirms earlier studies in one mouse strain. These findings support the hypothesis that alcohol-induced

hyperhomocysteinemia is not simply a marker of disturbed one-carbon metabolism but reflects an integral aspect of the pathogenesis of steatohepatitis. The contribution of homocysteine-induced homocysteinylation, redox effects, or mass effect on SAH to lower SAM/SAH in mediating effects on ER stress or other epigenetic effects requires additional investigation. Additional Supporting Information may be found in the online version of this article. “
“Background: The production of reactive aldehydes such as 4-hydroxy-2-nonenal (4-HNE) is a key component of the patho-genesis in alcoholic liver disease (ALD). One consequence of ALD is altered cAMP kinase (AMPK) signaling resulting in dys-regulation of β-oxidation.