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.

肥胖会导致脂肪肝病，损害葡萄糖和脂质代谢，并增加冠状动脉的风险心脏病（CHD）。内源性性恐怖对于男性和女人的代谢健康很重要。但是，重大物种差异一直是定义内源性雌激素和雄激素会影响肥胖症的代谢和冠心病风险。在老年人中，以任何一种激素导致血脂异常，并通常增加CHD风险，这是小鼠中未经复制的生物学。一个关键物种差异是人类表达小鼠缺乏的胆汁胆汁酯转移蛋白（CETP）。使用小鼠转基因进行CETP，我们“人性化”了这一途径，发现CETP是雌激素和雄激素的有益葡萄糖调节作用。我们发现CETP转导雌激素和雄激素的独特且有害的脂质作用，没有CETP表达，建模就不可能人类生物学。 CETP如何指导肝脏和脂肪组织产生这些不同的作用。我们的总体假设是CETP通过将TG引导到脂肪和胆固醇来帮助燃料分配肝脏用肥胖使葡萄糖代谢有益，但激活性激素和固醇信号通路导致血脂异常。在这项修订的建议中，我们开发了特定组织的方法来定义肝脏和 CETP对葡萄糖代谢，脂质代谢和动脉粥样硬化的影响的脂肪机制肥胖。我们还提出了热调节这些途径的方法。减肥的努力常常失败。拟议的目的有助于朝着激活“健康肥胖”途径的范式转变。在AIM1中，我们建议增加肝或脂肪CETP音调，以重新建立“健康肥胖”作为一种替代体重减轻。在AIM2中，我们建议对CETP性激素轴进行治疗调节以防止性激素治疗的血脂异常。我们有CETP需要通过的试点数据 LDL受体影响性激素作用。在AIM3中，我们将定义LDL受体如何调节性激素作用。在每个目标中，我们都将使用最新的示踪剂方法简单地研究葡萄糖和 TG在体内通量，因此我们可以定义途径以在营养过量的情况下创建健康的生理。我们将在等热条件下评估动脉粥样硬化，从而在不阻止胆固醇通量的情况下加速该生物学。该项目着重于CETP和LDLR途径的治疗意义。我们的方法是在概念和技术上使用新颖的“人性化”鼠标模型和最先进的营养通量的测量以建立临床研究的基础。这些研究解决了重要的健康问题作者：1）确定有助于绝经前冠心病保护的途径女性。 2）定义CETP如何促进性骑士治疗对血脂异常的不利影响，并将其转化为治疗。 3）评估新型肝靶性雌激素治疗以减少脂肪肝。 4）评估临床上与LDLR改良药物如何通过雌激素治疗影响代谢结果。