Cobalamin-Dependent Metabolism and Steatotic Liver Disease

Recent findings underscore the ability of common metabolites to direct cell function and fate. Yet, our understanding of mitochondrial biology and signaling requires deeper knowledge of the physiological mechanisms in human health and disease. This is particularly true today, as rising obesity and diabetes rates are exacerbating the existing crisis of steatotic liver disease and its end-stage complications. One metabolite that has recently gained attention as a signaling molecule is methylmalonic acid (MMA), a byproduct of propionyl-CoA catabolism, which funnels metabolites from the breakdown of branched chain amino acids and lipids into the tricarboxylic acid cycle for replenishment. Vitamin B12 (cobalamin) deficiency and mutations in key propionate pathway enzymes, such as cobalamin adenosyltransferase (encoded by MMAB), lead to the accumulation of MMA. MMAB converts cobalamin to its biologically active form, which maintains flux to break down propionyl-CoA, and loss-of-function mutations lead to lethal metabolic defects and chronic liver disease in humans. Importantly, recent work identified MMAB as a key driver of a liver-specific gene regulatory co-expression network associated with altered blood lipid and glucose levels in humans, suggesting that MMAB may play a more fundamental role in coordinating appropriate physiological responses to nutrient availability. Concurrently, our group found that by modulating propionate byproducts (namely, MMA), hepatic MMAB serves as a negative feedback regulator of cholesterol biosynthesis. Our recent pilot data reveal that in humans and in preclinical mouse models of non-alcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH), hepatic MMAB expression is significantly downregulated. Further, MMA has recently been associated with advanced fibrosis risk in patients with NAFLD, but substantial work is needed to define the mechanistic underpinnings of these important physiological relationships. Here, we will execute an experimental plan with two specific aims to test our central hypothesis that hepatic MMAB is a key mitochondrial metabolic checkpoint that regulates cellular phenotype and behavior. We posit that excess cholesterol disrupts this sensing network in the liver, thereby increasing MMA levels and downstream intra- and extra-hepatic signaling in ways that increase the progression of NAFLD/NASH. Here, we propose to (1) Elucidate the role of hepatic cobalamin-dependent metabolism during the progression of steatotic liver disease and (2) Define the molecular mechanisms by which hepatic MMAB contributes to the progression of NAFLD/NASH. Successful completion of the proposed studies will provide critical preliminary data for a future R01 application, as my laboratory seeks to uncover mechanism-based therapeutic target(s) to treat steatotic liver disease.