CETP and Sex-Differences in Metabolic and Cardiovascular Disease

CETP 与代谢和心血管疾病的性别差异

• 批准号: 10407032
• 负责人: John Michael Stafford
• 金额: $ 48.26万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-15 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10407032
• 关键词: Address; Adipose tissue; Aftercare; Age; Amplifiers; Androgens; Animals; Area; Atherosclerosis; Biology; Body Weight decreased; Cardiovascular Diseases; Cholesterol; Cholesterol Esters; Clinical Research; Clinical Trials; Coronary heart disease; Data; Dependovirus; Diabetes Mellitus; Dyslipidemias; Estradiol; Estrogen Receptor alpha; Estrogen Therapy; Estrogens; Fatty Liver; Fatty acid glycerol esters; Female; GPER gene; Gene Deletion; Glucose; Goals; Gonadal Steroid Hormones; Health; Hepatic; High Density Lipoprotein Cholesterol; High Density Lipoproteins; Hormones; Human; Human Biology; Impairment; Insulin Resistance; Lead; Lipids; Liver; Low Density Lipoprotein Receptor; Measurement; Measures; Mediating; Menopause; Metabolic; Metabolic Diseases; Metabolism; Methods; Modeling; Mus; National Heart, Lung, and Blood Institute; Nutrient; Obesity; Outcome; Output; Pathway interactions; Pharmaceutical Preparations; Physiological; Physiology; Premenopause; Proteins; Risk; Rodent; Role; Sex Differences; Signal Pathway; Sterols; Therapeutic; Tissues; Tracer; Transgenic Mice; Translating; Triglycerides; United States National Institutes of Health; Very low density lipoprotein; Wild Type Mouse; Woman; activation-induced cytidine deaminase; cardiovascular risk factor; clinically relevant; deprivation; fatty liver disease; glucose metabolism; heart disease risk; human model; humanized mouse; improved; in vivo; inhibitor; innovation; knock-down; lipid metabolism; lipid transfer protein; lipidomics; liver metabolism; mRNA sequencing; male; men; mouse model; novel; obesity risk; oxidation; preservation; prevent; protective effect; protein expression; response; species difference

Obesity leads to fatty liver disease, impairs glucose and lipid metabolism, and increases the risk of coronary heart disease (CHD). Endogenous sex hormones are important for metabolic health in men and women. However, significant species differences have been an obstacle to defining how endogenous estrogens and androgens impact metabolism and CHD risk with obesity. In older humans, replacement strategies with either hormone lead to dyslipidemia, and often increased CHD risk, a biology not reproduced in mice. One key species difference is that humans express cholesteryl ester transfer protein (CETP), which mice lack. Using mice transgenic for CETP we “humanized” this pathway, and discovered that CETP is an amplifier of the beneficial glucose-regulating effects of both estrogens and androgens. We discovered that CETP transduces unique and harmful lipid effects of estrogens and androgens, not present without CETP expression, modeling human biology. How CETP directs the liver and adipose tissue to generate these divergent effects is not known. Our overarching hypothesis is that CETP aids fuel partitioning by directing TG to adipose and cholesterol to liver to benefit glucose metabolism with obesity, but activates sex-hormone and sterol signaling pathways that result in dyslipidemia. In this revised proposal we’ve developed tissue-specific approaches to define the liver and adipose mechanisms for CETP’s effects on glucose metabolism, lipid metabolism and atherosclerosis with obesity. We also propose methods to therapeutically modulate these pathways. Efforts at weight loss often fail. The AIMS proposed contribute to a paradigm shift toward activating a “healthy obesity” pathway. In AIM1 we propose to increase hepatic or adipose CETP tone to re-establish “healthy obesity” as an alternative to weight loss. In AIM2 we propose to therapeutically modulate the CETP sex-hormone axis to prevent dyslipidemia with sex hormone treatment. We have pilot data that CETP requires delivery of cholesterol through LDL receptor to influence sex hormone action. In AIM3 we will define how the LDL-receptor modulates sex hormone action. In each AIM we will use state-of-the-art tracer methods to simultaneously study glucose and TG flux in vivo so that we may define pathways to create healthy physiology in the setting of nutrient excess. We will assess atherosclerosis at isothermic conditions that accelerate this biology without blocking cholesterol flux. This project focuses on the therapeutic significance of the CETP and LDLR pathways. Our approach is conceptually and technically innovative using novel “humanized” mouse models and state-of-the-art measurements of nutrient fluxes to establish the basis for clinical studies. These studies address a significant health problem by: 1) Identifying a pathway that contributes to the dramatic CHD protection in premenopausal women. 2) Defining how CETP contributes to the unfavorable effects of sex hormone treatment on dyslipidemia, and translating this into therapeutics. 3) Evaluating novel liver-targeted estrogen treatments to reduce fatty liver. 4) Evaluating how clinically-relevant LDLR-modifying drugs impact metabolic outcomes with estrogen treatment.

肥胖导致脂肪肝，损害葡萄糖和脂质代谢，并增加冠状动脉粥样硬化的风险。 心脏病（CHD）。内源性性激素对男性和女性的代谢健康很重要。 然而，显著的物种差异一直是确定内源性雌激素和 雄激素影响代谢和肥胖的CHD风险。在老年人中， 激素导致血脂异常，且常常增加CHD风险，这是一种不能在小鼠中复制生物学。一个关键物种 不同的是，人类表达胆固醇酯转移蛋白（CETP），而小鼠缺乏。 使用CETP转基因小鼠，我们“人源化”了这一途径，并发现CETP是一个放大器， 雌激素和雄激素的有益血糖调节作用。我们发现CETP可以转导 雌激素和雄激素的独特和有害的脂质作用，不存在CETP表达，建模 人类生物学CETP如何指导肝脏和脂肪组织产生这些不同的效果尚不清楚。 我们的总体假设是CETP通过将TG引导至脂肪和胆固醇引导至脂肪来辅助燃料分配。 肝脏有益于肥胖的葡萄糖代谢，但激活性激素和固醇信号通路， 导致血脂异常。在这个修订后的提案中，我们开发了组织特异性方法来定义肝脏， CETP对糖代谢、脂代谢和动脉粥样硬化的影响的脂肪机制， 肥胖我们还提出了治疗调节这些途径的方法。减肥的努力往往失败。 AIMS的提出有助于向激活“健康肥胖”途径的范式转变。 在AIM1中，我们建议增加肝脏或脂肪CETP张力，以重新建立“健康肥胖”， 替代减肥。在AIM2中，我们建议治疗性地调节CETP性激素轴，以防止 性激素治疗的血脂异常。我们有试点数据表明，CETP需要通过 LDL受体影响性激素作用。在AIM 3中，我们将定义LDL受体如何调节性 激素作用。在每个AIM中，我们将使用最先进的示踪方法同时研究葡萄糖和 TG通量在体内，以便我们可以定义的途径，创造健康的生理设置的营养过剩。我们 将评估动脉粥样硬化在等温条件下，加速这种生物学，而不阻止胆固醇流量。 该项目的重点是CETP和LDLR途径的治疗意义。我们的做法是 概念和技术创新，使用新的“人源化”小鼠模型和最先进的 测量营养通量，为临床研究奠定基础。这些研究解决了一个重要的 健康问题：1）确定一种途径，有助于显着的冠心病保护绝经前 妇女2)确定CETP如何导致性激素治疗对血脂异常的不利影响， 并将其转化为治疗方法。3)评估新型肝脏靶向雌激素治疗以减少脂肪肝。 4)评价临床相关的LDL受体调节药物如何影响雌激素治疗的代谢结果