Role of Acyl-coenzyme A: Cholesterol Acyltransferase in Adipocyte Function and Obesity
Abstract
Obesity is a global epidemic and is associated with enhanced risks of cardiovascular diseases (CVDs) and metabolic disorders. Strategies for obesity prevention and treatment are in great need. Obesity is characterized by fat mass expansion, which is determined mainly by increasing adipocyte number and lipid storage. Here, by targeting on adipogenesis and lipid storage, respectively, we investigated methods for a dietary prevention of obesity and a pharmacological treatment of obesity. For obesity prevention, we employed selenium supplementation, an essential micronutrient required for maintaining cellular redox homeostasis. In vitro results revealed the inhibition effect of selenate on adipogenesis, but its role in preventing the development of obesity and metabolic syndrome in vivo is unknown. We reported that chronic selenate supplementation at 0.72 mg/kg body weight dosage to high fat (HF) diet-fed mice resulted in resistance to diet-induced adiposity and insulin resistance. This was accompanied by the alteration of relative mRNA levels for genes associated with adipokines, inflammation, transforming growth factor-β (TGF-β) signaling, mitochondria function, and beige adipocyte differentiation in the adipose tissue. Selenate supplementation also resulted in an increase in fecal calorie content and improved glucose tolerance in HF diet-induced obese mice. For obesity treatment, we focused on acyl-coenzyme A: cholesterol acyltransferases (ACATs). ACAT, the enzyme that catalyze the formation of cholesteryl ester (CE) from free cholesterol (FC), has been identified as a therapeutic target to treat atherosclerosis. Given the key role of adipose tissue in storing FC in lipid droplets (LDs), however, the role of ACAT in adipogenesis, lipogenesis as well as LD formation, in adipocytes is unknown. Here, we found that inhibiting ACAT or knocking down ACAT1 or 2 significantly decreased the intracellular cholesterol level and de novo lipogenesis in adipocytes through downregulating sterol regulatory element-binding protein (SREBP)1 maturation process. Moreover, we found that daily intraperitoneal injection of an ACAT inhibitor for 13 days in diet induced obesity (DIO) mice resulted a ∼60% decrease in daily food intake with no hepatotoxicity, and a ∼20% of body weight (mainly fat mass) with improved diabetic status. Additionally, ACAT inhibition reduced the circulating serum leptin level by 88%, and resulted in reduced mRNA levels of genes involved in de novo lipogenesis and adipokines in the white adipose tissue (WAT). Indeed, a pair-feeding study revealed that the beneficial effect of ACAT inhibition in the tested mice was mainly attributed to the suppression of food intake, indicating a novel function of ACAT inhibition in food intake regulation. Taken together, our first study elucidated the role of selenate as a dietary micromineral in the prevention of obesity and its related energy dysfunction. Our second study revealed a novel function of ACAT in lipogenesis and highlights an important role of ACAT in integrating cholesterol metabolism and triglyceride synthesis in adipocytes. Moreover, we indicated the potential of ACAT inhibition as a therapeutic approach in treating obesity and its-related insulin resistance.
Degree
Ph.D.
Advisors
Kim, Purdue University.
Subject Area
Biology|Nutrition|Pharmaceutical sciences
Off-Campus Purdue Users:
To access this dissertation, please log in to our
proxy server.