The Role of Hmgcs2-mediated Ketogenesis in Non-alcoholic Fatty Liver Disease Development and Treatment

Abstract

Non-alcoholic fatty liver disease (NAFLD), described by the build-up of excess fat in the liver, is the most prevalent chronic liver condition globally. One of the essential metabolic functions of the liver is the production of ketone bodies, a process called, ketogenesis. Ketone bodies serve as alternative fat-derived sources of fuel for tissues under conditions of nutrient deficit (i.e., fasting). Interestingly, recent studies have found that ketogenesis is dysregulated in NAFLD patients. Similarly, we also found that high-fat diet-induced NAFLD mice exhibited diminished fasting-induced ketogenesis with reduced expression of liver Hmgcs2, the rate-limiting enzyme of ketogenesis. To understand the role of ketogenesis in NAFLD pathogenesis and treatment, we generated mouse models of ketogenic insufficiency and activation through Hmgcs2 loss- and gain-of-function, respectively. Notably, a change in dietary environment rescued the fatty liver phenotype of Hmgcs2 knockout mice and increased ketogenic function through HMGCS2 overexpression improved NAFLD-associated metabolic dysfunction and hepatosteatosis in adult mice. Furthermore, an untargeted metabolomics approach provided a comprehensive metabolic view underlying HMGCS2 overexpression-mediated NAFLD improvement, suggesting that hepatic ketogenesis impacts liver metabolism via regulation of other metabolic pathways. Together, our study adds new knowledge to the field of ketone body metabolism and suggests a viable therapeutic strategy involving ketogenesis activation in the prevention and treatment of NAFLD.