Effect of reduced expression by adeno-associated virus of the estrogen receptor alpha on hepatic metabolism

Abstract

Lifestyle and, more precisely, the increase in consumption of a high-fat diet contribute largely to the development of obesity, insulin resistance, type 2 diabetes (DM2) and cardiovascular diseases (1). The set of these abnormalities is usually called a metabolic syndrome, and the central factor of this syndrome is usually the insulin resistance associated with obesity. Several mechanisms are currently considered to cause insulin resistance, such as abnormal lipid metabolism and ectopic accumulation (2), mitochondrial dysfunction (3), in addition to inflammation and endoplasmic reticulum stress (4). One of the consequences of the Western lifestyle and high-fat diet is Non-Alcoholic Fatty Liver Disease (NAFLD), which affects about 30% of adults and up to 10% of children in developed countries (5). NAFLD starts with the accumulation of triacylglycerides (TAG) in the liver and is defined as the presence of lipid droplets in the cytoplasm of more than 5% of hepatocytes (6). One of the major concerns with NAFLD is that the accumulation of liver lipids has been clearly linked to the development of liver resistance to insulin and DM2. It has been suggested that metabolically beneficial actions of estradiol are mediated by the estrogen alpha receptor (ER±), since mice that do not have this receptor also have obesity (7). Recently, ER± activation has been shown to increase mitochondrial activity and systemic metabolism, protecting ovariectomized female mice against obesity induced by a high-fat diet (8). This effect of ER± on mitochondrial metabolism has also been demonstrated specifically in skeletal muscle (9).Thus, the general objective of this project is to study the effects of reduced expression of ER± by associated adeno virus on hepatic energy metabolism in mice. The specific objectives will be: Assess in vivo the effects of increased expression of ER± in the liver on; 1. Accumulation of lipids (TAG, DAG and ceramides); 2. Gene and protein expression of inflammatory markers; 3. Glucose tolerance through glucose tolerance test (GTT); 4. Insulin resistance using an euglycemic-hyperinsulinemic clamp (using radioactive tracers to determine glucose metabolism in vivo); 5. Global energy metabolism through indirect calorimetry. (AU)