Mechanisms of Diet-induced Dyslipidemia and Insulin Resistance: Role of Chronic LXR Activation

The metabolic syndrome is a collection of pathologies including dyslipidemia, obesity and insulin resistance. A thorough understanding of the mechanisms behind metabolic syndrome development would help in the development of treatment and prevention strategies. Our lab has previously shown that cholesterol feeding exacerbates features of the metabolic syndrome in high fat-, high fructose-fed mice. The nuclear receptor Liver X Receptor (LXR), a master transcriptional regulator of cholesterol, fat and carbohydrate metabolism in the liver, is endogenously activated by oxysterols, metabolic derivatives of cholesterol. In order to determine whether cholesterol exerts its metabolic effects via LXR activation, parallel studies were conducted comparing chronic cholesterol supplementation with LXR activation in the hamster. Results showed that cholesterol feeding and LXR activation caused similar dyslipidemia, glucose intolerance and upregulation of target mRNA and proteins. These data support the hypothesis that the dyslipidemic effects of dietary cholesterol are mediated at least in part by LXR.MAS