Insulin Regulation of Liver X Receptor in Normal and Insulin Resistant States

描述（由申请人提供）：心血管疾病（CVD）是美国发病率和死亡率的主要原因。肥胖和代谢综合征相关的胰岛素抵抗影响着超过三分之一的美国成年人，导致脂肪生成增加、高甘油三酯血症和心血管疾病风险增加两倍以上。然而，胰岛素抵抗增加心血管疾病的分子和机制尚不清楚。肝X受体（LXR）是一种核受体，在控制脂质和胆固醇代谢中起核心作用。据推测，LXR在高胰岛素血症的肥胖肝脏中被激活，因为LXR的脂肪生成靶点，如固醇反应元件结合蛋白1c (SREBP1c)，主要的脂肪生成转录因子，以LXR依赖的方式被组成性激活。然而，LXR胆固醇外排靶点，如ATP结合盒转运体ACBG5和ABCG8，在胰岛素抵抗状态下不会被诱导。因此，我们假设胰岛素选择性激活LXR诱导其脂肪生成靶点转录的能力，并且这种调节在胰岛素抵抗状态下保持活跃。本研究的目的是确定胰岛素如何调节LXR，这种调节在胰岛素抵抗状态下是如何改变的，以及LXR对胰岛素抵抗状态下观察到的脂肪生成和胆固醇外排基因表达变化的贡献。因此，我们建议首先确定胰岛素在K99期激活LXR的信号通路和机制。有了这些知识，我们将确定胰岛素抵抗如何在R00期调节脂肪生成和胆固醇外排基因中差异地改变LXR活性。我们期望我们提出的研究结果将为胰岛素抵抗状态下脂质和胆固醇代谢的转录控制提供重要的见解，并可能提供胰岛素抵抗促进心血管疾病的新机制。此外，通过了解脂肪生成和胆固醇外排靶点的转录如何被解离，我们可能能够开发出新的疗法，通过LXR选择性地激活胆固醇外排靶点，而不激活脂肪生成。

DESCRIPTION (provided by applicant): Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in the United States. Obesity and metabolic syndrome-associated insulin resistance, which affects more than one third of adults in the US, causes increased lipogenesis, hypertriglyceridemia and a greater than 2-fold increase in the risk of CVD. However, the molecules and mechanisms by which insulin resistance increases CVD are not clear. Liver X receptor (LXR) is a nuclear receptor which plays a central role in control of both lipid and cholesterol metabolism. LXR is presumably activated in the hyperinsulinemic, obese liver since the lipogenic targets of LXR, such as sterol response element binding protein 1c (SREBP1c), the master lipogenic transcriptional factor, are constitutively activated in a LXR-dependent manner. However, LXR cholesterol efflux targets, such as the ATP binding cassette transporters, ACBG5 and ABCG8, are not induced in insulin resistant states. Thus, we hypothesize that insulin selectively activates the ability of LXR to induce transcription of its lipogenic targets and that this regulation remains active in insulin resistant state. The objective of this proposal are to determine how insulin regulates LXR, how this regulation is changed in insulin resistant states and the contribution of LXR to the changes in lipogenic and cholesterol efflux gene expression observed in insulin resistant states. Thus we propose to first identify the signaling pathways and mechanisms by which insulin activates LXR in the K99 phase. With such knowledge we will then determine how insulin resistance differentially modifies LXR activity in the regulation of lipogenesis and cholesterol efflux genes in the R00 phase. It is our expectation that the results of our proposed studies will provide important insights into the transcriptional control of lipid and cholesterol metabolism in the insulin resistant state and potentially provide a novel mechanism by which insulin resistance promotes CVD. Moreover, by understanding how transcription of the lipogenic and cholesterol efflux targets can be dissociated, we may be able to develop novel therapies to selectively activate the cholesterol efflux targets via LXR, without activating lipogenesis.