CETP and Sex-Differences in Metabolic and Cardiovascular Disease

CETP 与代谢和心血管疾病的性别差异

基本信息

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
项目类别：
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

项目摘要

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.

肥胖会导致脂肪肝，损害葡萄糖和脂质代谢，并增加冠状动脉的风险心脏病（CHD）。内源性激素对于男性和女性的代谢健康都很重要。然而，显着的物种差异一直是定义内源性雌激素和雌激素如何发挥作用的障碍。在老年人中，雄激素会影响肥胖的新陈代谢和冠心病风险。激素会导致血脂异常，并常常增加冠心病的风险，这是一种在小鼠体内无法复制的生物学特性。不同之处在于，人类表达胆固醇酯转移蛋白（CETP），而小鼠则缺乏这种蛋白。使用 CETP 转基因小鼠，我们将该通路“人性化”，并发现 CETP 是我们发现 CETP 可以转导雌激素和雄激素的有益葡萄糖调节作用。雌激素和雄激素独特且有害的脂质效应，如果没有 CETP 表达、建模，则不存在 CETP 如何指导肝脏和脂肪组织产生这些不同的作用尚不清楚。我们的首要假设是，CETP 通过将 TG 引导至脂肪并将胆固醇引导至脂肪来帮助燃料分配。肝脏有利于肥胖患者的葡萄糖代谢，但会激活性激素和甾醇信号通路，从而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和血脂异常。 CETP影响糖代谢、脂代谢和动脉粥样硬化的脂肪机制我们还提出了治疗性调节这些途径的方法，以减轻体重。 AIMS 提议有助于实现激活“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 音调，以重新建立“健康肥胖”作为在 AIM2 中，我们建议通过治疗性调节 CETP 性激素轴来预防。我们有试点数据表明，CETP 需要通过性激素输送胆固醇。 LDL 受体影响性激素作用在 AIM3 中，我们将定义 LDL 受体如何调节性别。在每个 AIM 中，我们将使用最先进的示踪方法来同时研究葡萄糖和激素作用。体内 TG 通量，以便我们可以定义在营养过剩的情况下创造健康生理的途径。将在等温条件下评估动脉粥样硬化，从而加速这种生物学过程而不阻碍胆固醇流动。该项目重点关注 CETP 和 LDLR 途径的治疗意义。使用新颖的“人性化”小鼠模型和最先进的技术在概念和技术上进行创新营养通量的测量为临床研究奠定了基础。通过以下方式解决健康问题： 1) 确定有助于显着预防绝经前冠心病的途径 2) 定义 CETP 如何导致性激素治疗对血脂异常的不利影响， 3) 评估新型肝脏靶向雌激素治疗方法以减少脂肪肝。 4) 评估临床相关的 LDLR 修饰药物如何影响雌激素治疗的代谢结果。