Abstract 15393: Cholesterol Esterifying Enzyme Acat2 - A Target for Cardiometabolic Diseases

Abstract

Introduction and Hypothesis: The cholesterol esterifying enzyme acyl-Coenzyme A: cholesterol acyltransferase 2 (ACAT2, encoded by Soat2) is exclusively expressed in enterocytes and hepatocytes. Soat2-/- mice do not develop atherosclerosis or diet-induced hypercholesterolemia, and accumulate less triglycerides and cholesteryl esters in the liver (hepatic steatosis) when fed a high fat-cholesterol diet. Hepatocyte nuclear factor 1α and 4α play important roles in lipid and carbohydrate metabolism and function as positive regulators of the human SOAT2 gene. This together with the association between hepatic steatosis and insulin resistance, prompted us: 1) to investigate the role of ACAT2 in hepatic steatosis and a potential association between ACAT2 and insulin sensitivity, 2) to assess the effects of different dietary regimens, and 3) to study potential sex-related differences. Methods: Wild type and Soat2-/- mice were either fed a high-fat (but low in cholesterol), a high-carbohydrate, or a chow diet. Serum, liver, adipose and muscle tissues were analyzed. Oral glucose and insulin tolerance tests were performed. Plasma from humans bearing a rare exonic variant was analyzed. Results: Soat2-/- mice fed a high-fat diet for eight weeks develop less hepatic steatosis, were more insulin sensitive, had lower hepatic expression of glucose transporter 2 and fat specific protein 27 (FSP27, named Cidec in humans). Similar findings were present in Soat2-/- mice fed a high-carbohydrate diet for two weeks. Carrier of a rare exonic variant in CIDEC (rs140125102, Pro73Thr) had lower insulin and HOMA-IR compared to non-carriers. Conclusions: Genetic depletion of ACAT2 dramatically reduces hepatic steatosis and improves insulin sensitivity via downregulation of hepatic FSP27/Cidec expression independently of sex and diets. Inhibition of ACAT2 may thus be a strategy to treat cardiometabolic diseases.