Cholesteryl ester transfer protein, a novel mediator of insulin sensitivity

胆固醇酯转移蛋白，一种新型胰岛素敏感性介质

基本信息

批准号：
8633281
负责人：
John Michael Stafford
金额：
--
依托单位：
VETERANS HEALTH ADMINISTRATION
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-10-01 至 2017-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8633281
关键词：
Antisense Oligonucleotides Bile Acid Biosynthesis Pathway Bile Acids Bile fluid Body Weight decreased Cardiovascular Diseases Cardiovascular system Cessation of life Cholesterol Esters Clinic Commit Development Diabetes Mellitus Diet Disease Enrollment Estradiol Estrogen Receptor alpha Estrogens Euglycemic Clamping Failure Fatty Acids Fatty acid glycerol esters Female Figs - dietary Gene Proteins Genes Gluconeogenesis Glucose Clamp Health Health Personnel Healthcare Systems Hepatic High Density Lipoprotein Cholesterol High Density Lipoproteins High Prevalence Human Individual Insulin Insulin Resistance Knock-out Link Lipoproteins Liver Mediating Mediator of activation protein Metabolic Metabolism Modeling Mouse Protein Mus Muscle Obesity Ovariectomy Overweight Pathway interactions Patients Phenotype Phosphoenolpyruvate Carboxylase Population Protein Inhibition Proteins Regulation Risk Role Serum Sex Characteristics Signal Pathway Signal Transduction System Techniques Testing Tissues Transgenic Mice Triglycerides United States Very low density lipoprotein Veterans base diabetes risk feeding glucose metabolism glucose tolerance human CETP protein human disease improved in vivo innovation insulin sensitivity knock-down lipid metabolism male network models novel prevent promoter protective effect protein expression public health relevance sensor small heterodimer partner protein therapeutic target tool transcriptomics

项目摘要

DESCRIPTION (provided by applicant): Death and disease from obesity largely result from insulin resistance and diabetes. Weight-loss strategies are too often ineffective. Targeting pathways to improve insulin sensitivity with obesit may reduce risk of diabetes and cardiovascular disease; but such pathways have been elusive. We discovered a novel pathway mediated by cholesteryl ester transfer protein (CETP) that prevents insulin resistance, even with obesity. CETP shuttles triglycerides and cholesteryl esters between serum lipoproteins (VLDL and HDL), and tissues including liver. Pharmacological CETP inhibition raises HDL cholesterol but does not protect against cardiovascular disease. This failure may suggest non-HDL functions of CETP. Mice naturally lack CETP expression, so our lab used CETP transgenic mice to define how obesity impacts HDL protein composition. Our studies led to the surprising finding that constitutive CETP expression protected mice from high-fat diet (HFD)-induced insulin resistance -by insulin clamp techniques. This protection was despite becoming obese. We used an innovative approach where we integrated in vivo metabolism techniques with systems-based tools in order to define the mechanism for CETP-mediated protection from insulin resistance. CETP promotes bile secretion, so we profiled metabolites from CETP mice and found that increased liver and serum bile acids associated with insulin sensitivity. We also found increased gut bile acids that recirculate to the liver and led to activation of the hepatic bile-sensor FXR and small heterodimer partner (SHP). With transcriptional profiling we found CETP augments bile signaling, and enhances insulin-suppression of gluconeogenic genes in the liver. Female CETP mice had a greater improvement in insulin sensitivity than males, which was linked to an altered network of genes that increase estradiol levels and promote estrogen signaling in the liver. We hypothesize that CETP expression promotes insulin sensitivity by increasing bile acid secretion and bile acid signaling in the liver. We propose that CETP also promotes estrogen signaling, which is required for the full protective effects of CETP. We will explore these novel metabolic effects of CETP in 3 aims: In AIM1 we will use transgenic mice expressing CETP driven by the human gene promoter to test the hypothesis that induction of CETP with obesity protects from HFD-induced insulin resistance by activating bile signaling pathways. In AIM2 we will define if hepatic estrogen signaling is required for CETP-mediated insulin sensitivity using mice with knock-out of the estrogen receptor alpha. We expect to define important pathways that contribute to sex-differences in glucose and lipid metabolism. In AIM3 we will focus on the bile signaling pathway, and how CETP activates SHP. Using intergrated metabolite and transcriptional network models, we expect to discover pathways that can be targeted to generate a "metabolically healthy" obese phenotype. These innovative studies will be an important step towards preventing insulin resistance and diabetes associated with obesity, which are a major health burden to the US Veteran population.

描述（由申请人提供）：肥胖引起的死亡和疾病很大程度上是由胰岛素抵抗和糖尿病造成的。减肥策略往往是无效的。针对肥胖改善胰岛素敏感性的途径可能会降低患糖尿病和心血管疾病的风险；但这样的途径一直难以捉摸。我们发现了一种由胆固醇酯转移蛋白 (CETP) 介导的新途径，可以预防胰岛素抵抗，甚至在肥胖的情况下也是如此。 CETP 在血清脂蛋白（VLDL 和 HDL）和包括肝脏在内的组织之间传递甘油三酯和胆固醇酯。药理学 CETP 抑制会升高 HDL 胆固醇，但不能预防心血管疾病。此失败可能表明 CETP 的非 HDL 功能。小鼠天然缺乏 CETP 表达，因此我们的实验室使用 CETP 转基因小鼠来确定肥胖如何影响 HDL 蛋白组成。我们的研究得出了令人惊讶的发现，即通过胰岛素钳技术，组成型 CETP 表达可以保护小鼠免受高脂饮食 (HFD) 诱导的胰岛素抵抗。尽管变得肥胖，但这种保护仍然存在。我们采用了一种创新方法，将体内代谢技术与基于系统的工具相结合，以确定 CETP 介导的胰岛素抵抗保护机制。 CETP 促进胆汁分泌，因此我们分析了 CETP 小鼠的代谢物，发现肝脏和血清胆汁酸增加与胰岛素敏感性相关。我们还发现肠道胆汁酸增加，再循环到肝脏，导致肝胆汁传感器 FXR 和小异二聚体伴侣 (SHP) 的激活。通过转录分析，我们发现 CETP 增强了胆汁信号传导，并增强了肝脏中糖异生基因的胰岛素抑制。雌性 CETP 小鼠的胰岛素敏感性比雄性小鼠有更大的改善，这与增加雌二醇水平并促进肝脏中雌激素信号传导的基因网络改变有关。我们假设 CETP 表达通过增加肝脏中的胆汁酸分泌和胆汁酸信号传导来促进胰岛素敏感性。我们认为 CETP 还可以促进雌激素信号传导，这是 CETP 充分保护作用所必需的。我们将在 3 个目标中探索 CETP 的这些新颖的代谢作用：在 AIM1 中，我们将使用由人类基因启动子驱动的表达 CETP 的转基因小鼠来测试以下假设：肥胖诱导 CETP 可通过激活胆汁信号通路来防止 HFD 诱导的胰岛素抵抗。在 AIM2 中，我们将使用雌激素受体 α 敲除的小鼠来定义 CETP 介导的胰岛素敏感性是否需要肝脏雌激素信号传导。我们期望定义导致葡萄糖和脂质代谢性别差异的重要途径。在 AIM3 中，我们将重点关注胆汁信号通路以及 CETP 如何激活 SHP。使用整合的代谢物和转录网络模型，我们期望发现可以靶向产生“代谢健康”肥胖表型的途径。这些创新研究将是预防胰岛素抵抗和与肥胖相关的糖尿病的重要一步，肥胖是美国退伍军人的主要健康负担。