Bioenergetic mechanisms of alcohol-associated cirrhosis in patient derived hepatocytes

One in five heavy drinkers develop alcohol-associated cirrhosis. Metabolism, inflammation, signaling, gut microbiome and genetic variations have all been tied to pathogenesis but alcohol-associated cirrhosis (AC) models in rodents are limited by differences between rodent species and humans in genetic background and bioenergetics. Here, we used iPSC derived hepatocytes (iHLCs) as a tool to understand mechanisms of AC injury, hypothesizing that iHLC's derived from patients would preserve genetic and bioenergetic differences leading to AC, and as compared to iHLC's from patients free of liver disease. Bioenergetically, AC iHLCs had lower spare capacity for mitochondrial respiration and produced less ATP. Metabolic capacities of AC iHLC mitochondria for glutamine and fatty acids were reduced. Together with genome wide association (GWAS) studies, these metabolic and histologic profiles of AC derived iHLCs suggest that differences in mitochondrial oxidative phosphorylation and lipid droplet formation predispose to AC. Overall design: Hepatocyte was derived from patient derived iPSC