Population Studies Revealed Sex-Specific Roles of MIC25/CHCHD6 in Promoting NAFLD

Abstract

One of the major complications of metabolic syndrome affecting the liver, in the absence of excessive alcohol, is non-alcoholic fatty liver disease (NAFLD). It is estimated that 20-30% of the population worldwide are affected by NAFLD. Recent studies have revealed that NAFLD is more prevalent in men than women, with men exhibiting severe NAFLD symptoms. As of now, there are no prevention and/or treatment options for NAFLD other than reducing the risk factors such as weight reduction. To this end, we used our ~100 diverse inbred strains of mice and identified MIC25 or CHCHD6, a core component of MICOS (mitochondrial contact site and cristae organizing system) complex, as a causal gene in mediating NAFLD. We also observed dramatic differences in the regulation and functions of MIC25 between sexes. Specifically, MIC25 expression was downregulated in females via estrogen and is strongly associated with NAFLD severity. We followed up by investigating the mechanistic roles of MIC25 using loss- and gain-of-function mouse models. In a steatosis mouse model, MIC25 silencing ameliorates plasma cholesterol levels, insulin resistance, and intrahepatic triglyceride accumulation, while MIC25 overexpression exacerbates them. Stable isotope tracing analyses revealed that MIC25 also regulated carbon flux through mitochondrial pyruvate carboxylase and glucose anaplerosis, thereby affecting de novo lipogenesis, fat and glutamine oxidation, and gluconeogenesis accompanied by mitochondrial dysfunction/maladaptation. Given the need for a promising NAFLD drug candidate with personalized therapeutic potential, we feel that our novel findings will be of considerable interest to the liver scientific community. R00DK120875. This is the full abstract presented at the American Physiology Summit 2024 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.