ATP-CITRATE LYASE AS A THERAPEUTIC TARGET IN NON-ALCOHOLIC STEATOHEPATITIS

Abstract

Non-alcoholic fatty liver disease (NAFLD) prevalence is increasing concurrently with obesity, type 2 diabetes (T2D), and cardiovascular diseases (CVDs), with 1 in 4 people being affected. NAFLD is the leading cause of chronic liver disease globally and yet there are still no approved therapeutics for its treatment. NAFLD is characterized by excessive accumulation of hepatic lipids and represents a continuum of pathologies, including fatty liver, non-alcoholic steatohepatitis (NASH) and hepatic fibrosis. The presence of NASH and hepatic fibrosis predict the risk of developing liver cirrhosis, hepatocellular carcinoma (HCC), and liver failure. In addition to these liver-related pathologies, NASH is also closely linked to the pathogenesis of obesity, T2D, and CVDs, the latter being the leading cause of death in NAFLD patients. It has thus become critical to develop new therapies for NASH. A known contributor to NASH is elevated liver de novo lipogenesis (DNL), which can be inhibited by targeting acetyl-CoA carboxylase (ACC). However, hypertriglyceridemia limits the use of pharmacological ACC inhibitors as a monotherapy. ATP-citrate lyase (ACLY) sits upstream of ACC and generates acetyl-CoA and oxaloacetate from citrate. Whether inhibition of ACLY is effective for treating NASH is unknown. The studies in this dissertation describe the characterization of a new mouse model that replicates many of the pathological and molecular drivers of NASH in humans. In this model, genetically inhibiting ACLY in hepatocytes reduces liver malonyl-CoA, oxaloacetate, steatosis and ballooning as well as blood glucose, triglycerides, and cholesterol. Pharmacological inhibition of ACLY mirrors genetic inhibition but has additional positive effects on hepatic stellate cells, liver inflammation and fibrosis. Mendelian randomization analysis demonstrates that human variants that mimic reductions in ACLY, associate with lower circulating triglycerides and biomarkers of NASH. These data indicate that inhibiting liver ACLY may be an effective approach for the treatment of NASH and dyslipidemia.