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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：
10184832
负责人：
John Michael Stafford
金额：
$ 43.25万
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/10184832
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 Fruit Funding Glucagon Glucose Glycogen Goals Hepatic Hepatocyte High Density Lipoprotein Cholesterol High Density Lipoproteins Human Hyperglycemia 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 Oxides 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 base 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.

肥胖损害糖和脂质代谢，增加冠心病（CHD）的风险。女性