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）：