Therapeutic Potential of Estrogen-Regulated Metabolism and Cardiovascular Risk

雌激素调节代谢和心血管风险的治疗潜力

• 批准号: 10618133
• 负责人: John Michael Stafford
• 金额: $ 42.01万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-03-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10618133
• 关键词: Anti-Inflammatory Agents; Area; Atherosclerosis; Attenuated; Binding Proteins; Biology; Carbohydrates; Cardiovascular Diseases; Cholesterol; Chronic; Clinical Trials; Closure by clamp; Coronary heart disease; Dependence; Diabetes Mellitus; Diphtheria Toxin; Disease; Estradiol; Estrogen Receptor alpha; Estrogens; Fatty Liver; Fatty acid glycerol esters; Female; Funding; Glucagon; Glucose; Glycogen; Goals; Hepatic; Hepatocyte; High Density Lipoprotein Cholesterol; High Density Lipoproteins; Human; Hyperglycemia; Hyperinsulinism; Impairment; Isotopes; Knock-out; Knowledge; Link; Lipids; Liver; Long-Term Effects; Mediating; Menopause; Metabolic; Metabolic Diseases; Metabolism; Modeling; Mus; National Institute of Diabetes and Digestive and Kidney Diseases; Nutrient; Obesity; Obesity associated disease; Outcome; Output; Pathway interactions; Peptides; Physiology; Play; Prevalence; Property; Response Elements; Risk; Risk Factors; Sex Differences; Side; Signal Transduction; Stress; Techniques; Testing; Therapeutic; Tissues; Tracer; Triglycerides; United States National Institutes of Health; Very low density lipoprotein; Woman; atheroprotective; cardiovascular risk factor; diabetic; diet-induced obesity; estrogenic; fatty acid oxidation; glucose metabolism; glycemic control; heart disease risk; improved; innovation; insulin sensitivity; lipid biosynthesis; lipid metabolism; male; men; mouse model; pre-clinical; protective effect; protein activation; reverse cholesterol transport; sex; therapeutic target

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.

肥胖损害糖和脂质代谢，增加冠心病（CHD）的风险。妇女 患冠心病的风险是肥胖男性的1/2。冠心病的风险随着绝经而上升， 与肥胖男性不同的机制雌激素信号在女性中赋予的保护作用随着年龄的增长而丧失。 糖尿病是由于不确定的机制。肝脏在雌激素调节的代谢中起重要作用。我们 目标是治疗性靶向雌激素在男性和女性中的有益肝脏作用， 糖尿病与肝脏雌激素信号相互作用的机制使女性处于高冠心病风险中。 在这个项目的上一个资助周期中，我们使用小鼠模型和代谢示踪剂发现雌激素 通过肝脏雌激素受体α（ER α）的信号传导可以防止肥胖的几个关键方面， 相关代谢疾病。我们发现，1）全身和肝脏胰岛素敏感性改善; 2）脂肪 通过增加脂肪酸氧化和增加肝脏VLDL输出来减少肝脏; 3）动脉粥样硬化， 通过改善HDL的胆固醇流出和抗炎特性，以及通过增加肝脏 胆固醇转运（逆向胆固醇转运）。在检查肝脏ER α赋予肝脏ER α的途径时， 对于女性的保护作用，我们令人惊讶地观察到它对肥胖男性也有保护作用。 男性肝脏ER α，1）减少肝脏脂肪; 2）改善肝脏和全身胰岛素敏感性; 3）改善 HDL胆固醇流出能力。AIM 1的目的是放大肝脏ER α在男性中的有益作用。 和雌性小鼠通过定义治疗靶向肝脏中雌激素信号传导的方法。 女性糖尿病患者与男性糖尿病患者的冠心病风险相同。我们发现高血糖会导致 肝脏应激，否定了肝脏雌激素信号传导的益处。无论是高血糖还是 血糖控制是糖尿病否定作为女性的保护作用的机制， 被确定。我们将在AIM 2中探索这种重要生物学的机制。我们的首要假设是 靶向肝脏雌激素信号传导将有益于葡萄糖代谢、脂肪肝、HDL功能， 肥胖男女的动脉粥样硬化。相反，高血糖症导致肝脏葡萄糖积聚 这些代谢物激活碳水化合物反应元件结合蛋白并对抗ER α的益处。 我们的假设是创新的，因为我们提出，在肝细胞中靶向ER α将限制许多方面 肥胖相关疾病的女性和男性没有不利的雌激素作用于其他组织。 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，因为我们正在应用同位素示踪剂和组织靶向，性别为基础， 治疗，以区分雌二醇的作用和葡萄糖代谢在肝脏从深刻的全身效应。 我们的研究很重要，因为我们将利用性别差异生理学知识来制定有针对性的 对两性都有利的治疗方法。我们将确定一种将糖尿病与女性严重结局联系起来的途径。