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

• 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
• 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

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）： 肥胖导致的死亡和疾病主要是由胰岛素抵抗和糖尿病引起的。减肥策略往往无效。用obesit靶向途径改善胰岛素敏感性可能会降低糖尿病和心血管疾病的风险;但这种途径一直难以捉摸。我们发现了一种由胆固醇酯转移蛋白（CETP）介导的新途径，该途径可预防胰岛素抵抗，即使是肥胖症。 CETP在血清脂蛋白（VLDL和HDL）和组织（包括肝脏）之间穿梭甘油三酯和胆固醇酯。药理学CETP抑制提高HDL胆固醇，但不能预防心血管疾病。这种失败可能表明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蛋白质组成。我们的研究导致了令人惊讶的发现，组成型CETP表达保护小鼠免受高脂饮食（HFD）诱导的胰岛素抵抗-通过胰岛素钳夹技术。这种保护是尽管成为肥胖。 我们使用了一种创新的方法，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小鼠的代谢产物，发现肝脏和血清胆汁酸增加与胰岛素敏感性相关。我们还发现增加的肠胆汁酸再循环到肝脏，并导致肝脏胆汁传感器FXR和小异源二聚体伴侣（SHP）的激活。通过转录谱分析，我们发现CETP增强了胆汁信号传导，并增强了肝脏中促胰岛素基因的胰岛素抑制。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和促进肝脏雌激素信号传导的基因网络改变有关。 我们推测CETP表达通过增加肝脏中胆汁酸分泌和胆汁酸信号传导促进胰岛素敏感性。我们认为CETP还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的这些新的代谢作用：在AIM 1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肥胖诱导CETP通过激活胆汁信号传导途径保护HFD诱导的胰岛素抵抗的假设。在AIM 2中，我们将使用敲除雌激素受体α的小鼠来确定CETP介导的胰岛素敏感性是否需要肝脏雌激素信号传导。我们期望确定重要的途径，有助于性别差异的葡萄糖和脂质代谢。在AIM 3中，我们将专注于胆汁信号通路，以及CETP如何激活SHP。使用整合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肥胖相关糖尿病的重要一步，这是美国退伍军人人口的主要健康负担。