Aggravation of nonalcoholic steatohepatitis by moderate alcohol consumption is associated with decreased SIRT1 activity in rats

Chronic alcohol intake decreases adiponectin and sirtuin 1 (SIRT1) expressions, both of whichhave been implicated in various biological processes including inflammation, apoptosis and metabolism. Wehave previously shown that moderate consumption of alcohol aggravates liver inflammation and apoptosisin rats with pre-existing nonalcoholic steatohepatitis (NASH). This study investigated whether moderatealcohol intake alters SIRT1 activity, adiponectin/Adiponectin receptor (AdipoR)-related signaling and lipidmetabolism in a pre-existing NASH status. Sprague-Dawley rats were fed with a high-fat diet (71% energyfrom fat) for 6 weeks to induce NASH then subsequently divided into 2 sub-groups: fed either a modifiedhigh-fat diet (HFD, 55% energy from fat) or a modified high-fat alcoholic diet (HFA, 55% energy from fatand 16% energy from ethanol) for an additional 4 weeks. We observed in comparison to HFD group, HFAincreased hepatic nuclear SIRT1 protein but decreased its deacetylase activity. SREBP-1c protein expressionand FAS mRNA levels were significantly upregulated, while DGAT1/2 and CPT-I mRNA levels weredownregulated in the livers of HFA compared to HFD. Although hepatic AdipoR1 decreased, HFA did notalter AdipoR2 and their downstream signaling. There were no significant changes in plasma adiponectinand free fatty acids (FFA), as well as adiponectin expression in adipose tissue between the two groups. Thepresent study indicates that suppression in SIRT1 deacetylase activity contributes to alcohol-exacerbatedhepatic inflammation and apoptosis in rats with pre-existing NASH. In addition, moderate alcohol intake didnot modulate adiponectin/AdipoR signaling axis in this model.