Therapeutic Potential of Estrogen-Regulated Metabolism and Cardiovascular Risk

肥胖会损害糖和脂代谢，增加患冠心病的风险。女人 肥胖者患冠心病的风险约为肥胖男性的1/2。患冠心病的风险随着更年期的增加而增加，但到了 与肥胖男性不同的机制。雌激素信号在女性体内的保护作用随着 由于机制不明而导致的糖尿病。肝脏在雌激素调节代谢中起着重要作用。我们的 目标是针对雌激素对男性和女性的有益肝脏作用进行治疗，并发现 糖尿病与肝脏雌激素相互作用的机制，使女性处于CHD高危状态。 在这个项目的上一个资金周期中，我们使用了小鼠模型和代谢示踪剂来发现雌激素 通过肝脏雌激素受体α(ERA)发出的信号可以预防肥胖的几个关键方面- 相关的代谢性疾病。我们发现，1)全身和肝脏对胰岛素的敏感性得到改善；2)脂肪 肝脏通过增加脂肪酸氧化和增加肝脏极低密度脂蛋白的输出而减少；3)动脉粥样硬化 通过改善高密度脂蛋白的胆固醇外流和抗炎性能，以及通过增加肝脏 胆固醇输送(反向胆固醇输送)。在研究肝脏时代赋予的途径时 对于女性的保护，我们做出了令人惊讶的观察，它对肥胖的男性也有保护作用。 男性的肝期，1)降低肝脏脂肪；2)改善肝脏和全身的胰岛素敏感性；3)改善 高密度脂蛋白胆固醇流出能力。AIM1的目标是在男性中放大肝脏时代的有益影响 通过定义治疗靶向肝脏中的雌激素信号的方法，对雌性小鼠进行了研究。 糖尿病女性的冠心病风险与糖尿病男性相同。我们发现高血糖会导致 肝脏应激，否定了肝脏雌激素信号的益处。无论是高血糖还是某些方面的 血糖控制是糖尿病抵消女性遗体保护作用的机制。 要下定决心。我们将探索AIM2中这一重要生物学的机制。我们最重要的假设是 靶向肝脏雌激素信号将有益于葡萄糖代谢、脂肪肝、高密度脂蛋白功能，以及 肥胖男性和女性的动脉粥样硬化。相反，高血糖会导致肝脏葡萄糖蓄积。 激活碳水化合物反应元件结合蛋白的代谢物，并抵消ERA的好处。 我们的假设是创新的，因为我们提出肝细胞中的靶向era将限制许多方面。 肥胖相关疾病在女性和男性中都没有对其他组织产生不利的雌激素作用。 我们还将确定糖尿病对女性冠心病危险因素的性别特异性影响的关键机制。 我们的技术是创新的，因为我们应用了同位素示踪剂和组织靶向、基于性别的 区分雌激素在肝脏的作用和葡萄糖代谢与对全身的深远影响的治疗学。 我们的研究意义重大，因为我们将利用性别差异生理学知识来制定有针对性的 对两性都有好处的治疗。我们将定义一条将糖尿病与女性严重后果联系起来的途径。

Obesity impairs glucose and lipid metabolism and increases the risk of coronary heart disease (CHD). Women with obesity have ~1/2 the risk of CHD as obese men. The risk of CHD goes up with menopause, but by mechanisms distinct from obese men. The protection conferred by estrogen signaling in females is lost with diabetes due to undefined mechanisms. The liver plays an important part in estrogen-regulated metabolism. Our goal is to therapeutically target the beneficial hepatic actions of estrogens in males and females and discover the mechanisms by which diabetes interacts with liver estrogen signaling to put females at high CHD risk. In the last funding cycle of this project, we used mouse models and metabolic tracers to discover that estrogen signaling through hepatic estrogen receptor alpha (ERa) protects against several key aspects of obesity- associated metabolic disease. We showed that, 1) whole body and liver insulin sensitivity are improved; 2) fatty liver is diminished by increasing fatty acid oxidation and increasing liver VLDL output; 3) atherosclerosis is reduced by improving HDL’s cholesterol efflux and anti-inflammatory properties, and by increasing liver cholesterol delivery (reverse cholesterol transport). While examining the pathways by which hepatic ERa confers protection for females, we made the surprising observation that it has protective effects in obese males also. Hepatic ERa in males, 1) decreases liver fat; 2) improves liver and whole-body insulin sensitivity; 3) improves HDL cholesterol efflux capacity. The goal of AIM1 is to amplify the beneficial effects of the hepatic ERa in male and female mice by defining approaches to therapeutically target estrogen signaling in the liver. Diabetic women have the same elevated CHD risk as diabetic men. We found that hyperglycemia induces hepatic stress, negating the benefit of hepatic estrogen signaling. Whether hyperglycemia or some aspect of glycemic control is the mechanism by which diabetes negates the protective effect of being female remains to be determined. We will explore mechanisms for this important biology in AIM2. Our overarching hypothesis is that targeted hepatic estrogen signaling will benefit glucose metabolism, fatty liver, HDL function, and atherosclerosis in obese males and females. In contrast, hyperglycemia leads to accumulation of liver glucose metabolites that activate Carbohydrate Response Element Binding Protein and counters the benefits of ERa. Our hypothesis is innovative because we propose that targeting ERa in hepatocytes will limit many aspects of obesity-associated disease in both females and males without unfavorable estrogen actions on other tissues. We will also define a critical mechanism for the sex-specific impact of diabetes on CHD risk factors in females. Our techniques are innovative because we are applying isotopic tracers and tissue-targeted, sex-based, therapeutics to distinguish estradiol action and glucose metabolism at the liver from profound whole-body effects. Our studies are significant because we will use knowledge of sex differences physiology to develop targeted treatments that benefit both sexes. We will define a pathway that links diabetes to severe outcomes in women.