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: 8966663
• 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/8966663
• 关键词: Antisense Oligonucleotides; Bile Acid Biosynthesis Pathway; Bile Acids; Bile fluid; Body Weight decreased; CETP gene; Cardiovascular Diseases; Cardiovascular system; Cessation of life; Cholesterol Esters; Clinic; Development; Diabetes Mellitus; Disease; Enrollment; Estradiol; Estrogen Receptor alpha; Estrogens; Euglycemic Clamping; Failure; Fatty Acids; Female; Figs - dietary; Gene Proteins; Genes; Gluconeogenesis; Glucose Clamp; Health; Health Personnel; Healthcare Systems; Hepatic; High Density Lipoprotein Cholesterol; High Density Lipoproteins; High Fat Diet; 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 disease; improved; in vivo; innovation; insulin sensitivity; knock-down; lipid metabolism; male; network models; novel; prevent; promoter; protective effect; protein expression; sensor; 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很大程度上是由胰岛素抵抗和糖尿病引起的。减肥策略往往是无效的。靶向途径，以改善胰岛素敏感性的奥贝西特可能会降低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，即使是肥胖也是如此。CETP在血清脂蛋白(极低密度脂蛋白和高密度脂蛋白)和包括肝脏在内的组织之间运送甘油三酯和胆固醇酯。药物抑制CETP可提高高密度脂蛋白胆固醇，但不能预防心血管疾病。这一故障可能提示CETP的非高密度脂蛋白功能。小鼠天生缺乏CETP的表达，所以我们的实验室使用CETP转基因小鼠来确定肥胖如何影响高密度脂蛋白的组成。我们的研究发现，通过胰岛素钳技术，结构性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，但这种保护措施仍然有效。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，因此我们对CETP小鼠的代谢产物进行了分析，发现肝脏和血清胆汁酸的增加与胰岛素敏感性有关。我们还发现，再循环到肝脏的肠道胆汁酸增加，并导致肝脏胆汁传感器FXR和小异二聚体伙伴(SHP)的激活。通过转录图谱，我们发现CETP增强了胆汁信号，并增强了肝脏中糖异生基因的胰岛素抑制作用。雌性CETP小鼠在胰岛素敏感性方面比雄性小鼠有更大的改善，这与改变的基因网络有关，该基因网络增加了肝脏中的雌二醇水平，并促进了雌激素信号的传递。我们假设CETP的表达通过增加肝脏中胆汁酸的分泌和胆汁酸信号来促进胰岛素敏感性。我们认为CETP还促进雌激素信号转导，这是CETP发挥全面保护作用所必需的。我们将从三个方面探讨CETP的这些新的代谢作用：在AIM1中，我们将使用由人类基因启动子驱动的表达CETP的转基因小鼠来验证肥胖诱导CETP通过激活胆汁信号通路来保护高脂诱导的胰岛素抵抗的假说。在AIM2中，我们将利用雌激素受体α基因敲除的小鼠来确定CETP介导的胰岛素敏感性是否需要肝脏雌激素信号。我们希望确定导致性别差异的重要途径--葡萄糖和脂肪代谢的差异。在AIM3中，我们将重点介绍胆汁信号通路，以及CETP如何激活SHP。利用整合的代谢物和转录网络模型，我们希望发现可以有针对性地产生“代谢健康”肥胖表型的途径。这些创新研究将是朝着预防与肥胖相关的胰岛素抵抗和糖尿病迈出的重要一步，而肥胖和糖尿病是美国退伍军人的主要健康负担。