CETP and Sex-Differences in Metabolic and Cardiovascular Disease

肥胖会导致脂肪肝，损害糖和脂代谢，并增加患冠心病的风险 心脏病(CHD)。内源性性激素对男性和女性的新陈代谢健康很重要。 然而，显著的物种差异一直是定义内源性雌激素和 雄激素影响新陈代谢和肥胖的冠心病风险。在老年人中，使用任何一种替代策略 荷尔蒙会导致血脂紊乱，并经常增加患冠心病的风险，这是一种在小鼠身上不能复制的生物学特性。一个关键物种 不同的是，人类表达胆固醇酯转移蛋白(CETP)，而老鼠缺乏这种蛋白。 使用转基因CETP的小鼠，我们将这一途径人源化，并发现CETP是一种 雌激素和雄激素的有益的血糖调节作用。我们发现CETP转导 雌激素和雄激素的独特和有害的脂质效应，没有CETP表达就不存在，建模 人类生物学。CETP如何引导肝脏和脂肪组织产生这些不同的影响尚不清楚。 我们的主要假设是CETP通过引导甘油三酯到脂肪和胆固醇到脂肪来帮助燃料分配 肝脏有利于肥胖患者的葡萄糖代谢，但激活性激素和类固醇信号通路 会导致血脂异常。在这项修订的提案中，我们开发了组织特异性方法来定义肝脏和 CETP影响糖代谢、脂代谢和动脉粥样硬化的脂肪机制 肥胖。我们还提出了从治疗上调节这些通路的方法。减肥的努力常常失败。 提出的目标有助于将范式转变为激活“健康肥胖”途径。 在AIM1中，我们建议增加肝脏或脂肪CETP的基调，以重建作为一种 减肥的替代方案。在AIM2中，我们建议从治疗上调节CETP性激素轴，以防止 性激素治疗引起的血脂异常。我们有试点数据表明CETP需要通过 低密度脂蛋白受体影响性激素的作用。在AIM3中，我们将定义低密度脂蛋白受体如何调节性 荷尔蒙作用。在每个目标中，我们将使用最先进的示踪方法来同时研究葡萄糖和 体内的甘油三酯通量，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。我们 将在等温条件下评估动脉粥样硬化，这种条件可以加速这一生物学过程，而不会阻止胆固醇流动。 本项目重点研究CETP和LDLR通路的治疗意义。我们的方法是 概念和技术上的创新使用了新颖的“人性化”鼠标模型和最先进的 营养素通量的测量，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)找出绝经前显著保护冠心病的途径 女人。2)明确CETP如何导致性激素治疗对血脂异常的不利影响； 并将其转化为治疗学。3)评估新的肝脏靶向雌激素治疗方法以减少脂肪肝。 4)评估与临床相关的低密度脂蛋白受体修饰药物如何影响雌激素治疗的代谢结果。

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.