Chronic binge alcohol alters hepatic expression of metabolic genes in SIV-infected female rhesus macaques

Abstract

Background: Alcohol-related liver injury includes steatosis, fibrosis, and inflammation, which can culminate in alcoholic hepatitis and cirrhosis. The pre-clinical alterations in gene expression underlying these pathophysiological changes are ill-defined. Chronic binge alcohol (CBA) consumption produces marked alterations in metabolic processes and our studies show this is accentuated in chronic infection such as in HIV. This study tested the hypothesis that CBA disrupts expression of hepatic genes involved in glycolytic, gluconeogenic, and lipid turnover pathways in rhesus macaques infected with simian immunodeficiency virus (SIV). Methods: Female rhesus macaques were administered CBA (13-14g ethanol/kg/week, n=7) or vehicle (VEH, n=8) starting 3 months prior to SIV infection. All animals were treated with anti-retroviral therapy starting at 2.5 months post-SIV infection and sacrificed at 14.5 months and liver samples obtained for histological analysis, determination of gene expression by qPCR, triglyceride content by colorimetric assay, and pyruvate kinase activity by a colorimetric enzymatic assay. Results: Expression of lipid handling genes including perilipin 1, peroxisome proliferator-activated receptor γ (PPARγ), carbohydrate responsive binding protein (CHREBP), and acetyl-CoA carboxylase B were higher in CBA-treated compared to VEH-treated macaques. Expression of glycolytic (phosphofructokinase) and gluconeogenic (pyruvate carboxylase) enzymes including aldolase A was increased in the CBA group compared to VEH. No changes were observed in expression of the β-oxidation regulatory protein PPARα. Triglyceride content and pyruvate kinase activity were not significantly different between the groups. Conclusions: These results show significant CBA-mediated alteration of mRNA expression of lipid handling genes that could reflect increased lipid turnover despite lack of alterations in hepatic triglyceride content. Future studies will confirm the findings with protein expression of the differentially regulated genes and levels of non-esterified fatty acid in the liver. Supported by T32AA007577 & P60AA009803. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.