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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

基本信息

批准号：
10899800
负责人：
John Michael Stafford
金额：
$ 6.98万
依托单位：
VANDERBILT UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
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/10899800
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

项目摘要

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.

肥胖会损害葡萄糖和脂质代谢，并增加患冠心病（CHD）的风险。女性肥胖男性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，但机制与肥胖男性不同。女性雌激素信号所赋予的保护会随着雌性激素信号的丧失而消失由于机制不明而导致的糖尿病。肝脏在雌激素调节的代谢中起着重要作用。我们的目标是在治疗上针对男性和女性雌激素的有益肝脏作用，并发现糖尿病与肝脏雌激素信号相互作用的机制，使女性处于冠心病高风险中。在该项目的最后一个资助周期中，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 (ERa) 发出的信号可预防肥胖的几个关键方面—— 相关代谢性疾病。我们发现，1）全身和肝脏的胰岛素敏感性得到改善； 2) 脂肪通过增加脂肪酸氧化和增加肝脏 VLDL 输出来削弱肝脏； 3）动脉粥样硬化是通过改善 HDL 的胆固醇流出和抗炎特性以及增加肝脏功能来减少胆固醇输送（胆固醇逆向转运）。在检查肝脏 ERa 赋予的途径时在保护女性的同时，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ERa，1）减少肝脏脂肪； 2）提高肝脏和全身胰岛素敏感性； 3）改善 HDL 胆固醇流出能力。 AIM1 的目标是放大男性肝脏 ERa 的有益作用通过定义针对肝脏中雌激素信号传导的治疗方法，对雌性小鼠进行了研究。女性糖尿病患者患冠心病的风险与男性糖尿病患者相同。我们发现高血糖会导致肝脏应激，否定肝脏雌激素信号传导的益处。无论是高血糖还是某些方面血糖控制是糖尿病消除女性对健康的保护作用的机制。被确定。我们将在 AIM2 中探索这一重要生物学机制。我们的总体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 功能和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并抵消 ERa 益处的代谢物。我们的假设是创新的，因为我们提出靶向肝细胞中的 ERa 将限制许多方面女性和男性中与肥胖相关的疾病，而雌激素对其他组织没有不利的作用。我们还将定义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，因为我们应用同位素示踪剂和组织靶向、基于性别、区分雌二醇作用和肝脏葡萄糖代谢与全身影响的治疗方法。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开发有针对性的对两性都有益的治疗方法。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。