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; 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.

肥胖会损害葡萄糖和脂质代谢，并增加冠心病（CHD）的风险。女性 肥胖具有〜1/2的风险，即肥胖的男人。 CHD的风险与更年期相比，但 与肥胖男人不同的机制。女性中雌激素信号传导所提供的保护失去了 由于未定义的机制而引起的糖尿病。肝脏在雌激素调节的代谢中起重要作用。我们的 目标是热靶向男性和女性中雌激素的有益肝作用，并发现 糖尿病与肝脏雌激素信号相互作用的机制使雌性处于高冠心病风险。 在该项目的最后一个资金周期中，我们使用了鼠标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）发出信号可预防肥胖的几个关键方面 相关的代谢疾病。我们表明，1）全身和肝胰岛素敏感性得到提高； 2）脂肪 通过增加脂肪酸氧化并增加肝VLDL输出来减少肝脏； 3）动脉粥样硬化是 通过改善HDL的胆固醇外排和抗炎特性来降低，并增加肝脏 胆固醇递送（反向胆固醇运输）。在研究肝时代赋予的途径的同时 对女性的保护，我们令人惊讶地观察到它也保护了肥胖男性的影响。 男性肝时代，1）减少肝脏脂肪； 2）改善肝脏和全身胰岛素敏感性； 3）改进 HDL胆固醇外排能力。 AIM1的目的是扩大男性肝时代的有益作用 和雌性小鼠通过定义治疗方法靶向肝脏中的雌激素信号传导。 糖尿病妇女的冠心病风险与糖尿病男性相同。我们发现高血糖影响 肝应激，否定肝雌激素信号传导的益处。是高血糖还是 血糖控制是糖尿病否定女性受保护作用的机制 可以确定。我们将探索AIM2中这种重要生物学的机制。我们的总体假设是 靶向肝雌激素信号传导将使葡萄糖代谢，脂肪肝，HDL功能和 肥胖男性和女性的动脉粥样硬化。相反，高血糖导致肝葡萄糖的积累 激活碳水化合物响应元件结合蛋白并抵消ERA的好处的代谢产物。 我们的假设具有创新性，因为我们建议靶向肝细胞时代将限制许多方面 女性和男性肥胖相关疾病的疾病，对其他组织没有不利的雌激素作用。 我们还将为糖尿病对女性冠心病风险因素的性别特定影响定义一种关键机制。 我们的技术具有创新性，因为我们正在应用同位素示踪剂和靶向组织，基于性别， 疗法以区分肝脏作用和葡萄糖代谢与深度全身作用的葡萄糖代谢。 我们的研究很重要，因为我们将使用性别差异的知识生理来发展目标 受益于男女的治疗。我们将定义一条将糖尿病与女性严重预后联系起来的途径。