Nuclear Receptor Control of Glucose and Lipid Metabolism

描述（由申请人提供）：心血管疾病是糖尿病患者死亡的主要原因。尽管有大量的流行病学数据将糖尿病和心血管疾病联系起来，但高血糖促进动脉粥样硬化的分子机制仍然知之甚少。肝脏X受体（LXRs）是由氧化形式的胆固醇（氧甾醇）激活的转录因子，作为细胞内过量胆固醇积累的传感器。除了调节胆固醇和脂质稳态外，LXRs还调节葡萄糖代谢关键基因的表达。我们最近报道了令人惊讶的观察结果，葡萄糖可以结合LXR并激活体内LXR靶基因。它们结合葡萄糖和氧甾醇的能力提示LXRs可能代表了糖尿病高血糖状态和动脉粥样硬化之间的分子联系。拟议的研究将测试LXRs在体内作为双氧甾醇-葡萄糖传感器的想法。阐明这一作用有望增强我们对糖尿病和动脉粥样硬化之间的转录机制的理解。

DESCRIPTION (provided by applicant): Cardiovascular disease is the principal cause of death in patients with diabetes. In spite of ample epidemiological data linking diabetes and cardiovascular disease, the molecular mechanisms that underlie how hyperglycemia promotes atherosclerosis, remain poorly understood. The Liver X Receptors (LXRs) are transcription factors activated by oxidized forms of cholesterol (oxysterols) that serve as sensors of excessive intracellular cholesterol accumulation. In addition to their role in regulation of cholesterol and lipid homeostasis, the LXRs also modulate expression of key genes in glucose metabolism. We recently reported the surprising observation that glucose can bind the LXRs and activate LXR target genes in vivo. Their ability to bind both glucose and oxysterols hints that LXRs may represent a molecular connection between the diabetic hyperglycemic state and atherosclerosis. The proposed research will test the idea that LXRs act as dual oxysterol-glucose sensors in vivo. Elucidation of such a role is expected to enhance our understanding of the transcriptional mechanisms that link diabetes and atherosclerosis. Evaluation of the role of LXR as a dual oxysterol-glucose sensor will be facilitated by the identification of mutants that respond differentially to these two physiological ligands. Specific Aim 1 is to use modeling to isolate and characterize in cell-based and biochemical assays LXR mutants with altered ligand responses. To understand how LXR integrates metabolic signals from two nutrients, and to enable guided design of LXR mutants, in Specific Aim 2 we will elucidate the structural basis of the LXR-glucose-oxysterol interaction. In Specific Aim 3, the ability of LXR mutants with dissociated ligand responses to regulate endogenous LXR targets will be tested in cultured hepatocytes and selected mutants will be used to systematically profile the impact of LXR signaling on metabolic pathways. In Specific Aim 4, LXR mutants with altered ligand responses will be used to create using gene targeting animal models to dissect the role of LXR in glucose and cholesterol metabolism in vivo. The ultimate goal of these studies is to use animals with engineered mutations to test the role of LXRs as glucose-oxysterol sensors in vivo. Future studies with mice expressing mutant LXRs will test the in vivo significance of LXR as a link between diabetes and atherosclerosis. We expect this work to enhance our understanding of how diabetes accelerates atherosclerosis, and to suggest novel therapeutic approaches to treat these conditions. Cardiovascular disease is a major complication of diabetes that accounts for more than 70% of all deaths in patients with diabetes. The risk of cardiovascular mortality is four times higher in individuals with diabetes than in nondiabetic individuals with similar levels of serum cholesterol. The long term goal of the proposed research is to advance our understanding of the cellular and molecular mechanisms that link diabetes and cardiovascular disease.