Sexual dimorphism, hepatic mitochondrial adaptations, and hepatic steatosis

性别二态性、肝线粒体适应和肝脂肪变性

• 批准号: 9891404
• 负责人: John P Thyfault
• 金额: --
• 依托单位: KANSAS CITY VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-10-01 至 2023-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9891404
• 关键词: Ablation; Acetyl Coenzyme A; Aerobic Exercise; Affect; Attention; Automobile Driving; Bile Acid Biosynthesis Pathway; Bile Acids; Biogenesis; Cardiovascular Diseases; Cholesterol; Chronic; Cirrhosis; Clinical Data; Data; Diet; Enzymes; Estradiol; Estrogen Receptor alpha; Estrogens; Excretory function; Exercise; Fatty Acids; Fatty Liver; Fatty acid glycerol esters; Female; Genes; Genetic; Goals; Health; Hepatic; Hydrogen Peroxide; Impairment; Indirect Calorimetry; Injury; Knock-out; Knockout Mice; Link; Lipids; Liver; Liver Mitochondria; Malignant neoplasm of liver; Measures; Mediating; Mediator of activation protein; Membrane Potentials; Menopause; Metabolic; Metabolic stress; Mitochondria; Molecular; Mus; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Operative Surgical Procedures; Ovarian; Ovariectomy; Pathology; Patients; Pharmaceutical Preparations; Pharmacology; Physical Exercise; Physical activity; Population; Predisposition; Premenopause; Quality Control; Reactive Oxygen Species; Respiration; Risk; Risk Factors; Rodent; Rodent Model; Serum; Sex Differences; Signal Transduction; Skeletal Muscle; Steatohepatitis; Techniques; Testing; Veterans; War; Woman; Women' s Health; base; bile acid metabolism; cardiovascular risk factor; diet and exercise; fitness; in vivo; lipid biosynthesis; liver injury; male; men; non-alcoholic fatty liver; normal aging; novel; overexpression; oxidation; physical inactivity; prevent; respiratory; response; sedentary; sex; sexual dimorphism; small hairpin RNA; therapeutic target; trafficking; trait

Project Summary/Abstract Hepatic steatosis (fatty liver) is a risk factor for type 2 diabetes, cardiovascular disease, and further liver injury, all major health issues for Veterans. Currently there are 1.6 million women Veterans, a number predicted to grow steadily making women's health issues a major concern going forward. Prior to menopause, women are protected against steatosis, but risk dramatically increases after loss of ovarian function and accumulating evidence shows that differences in estrogen signaling are a primary mediator. Physical inactivity and low fitness also drive increased risk for hepatic steatosis and associated pathologies. In contrast, increased physical activity and exercise protects and treats steatosis, even in obese patients. Abnormalities in hepatic mitochondrial function strongly contribute to the pathology of steatosis and are likely a primary target for the effects of physical activity and exercise to mitigate the condition, but mechanisms remain largely unknown. Estrogen is likely the cause of protection against hepatic steatosis in female rodents but the direct effects of estrogen signaling on hepatic mitochondria function have received little attention. Our recent findings show that female mice display increased mitochondrial respiration, lower reactive oxygen species (H2O2) emission and protection against steatosis in a sedentary condition compared to males. Female hepatic mitochondria respiratory capacity was also more responsive to diet- and exercise-induced metabolic stress, but these adaptive traits were partially diminished in mice with genetic ablation of mitochondrial turnover (biogenesis and mitophagy). These data form our hypothesis that enhanced mitochondrial function in females is critical for their inherent protection against steatosis and adaptive responses to metabolic stress. We will test the hypothesis that estrogen signaling through estrogen receptor α (ERα) is obligatory for elevated hepatic mitochondrial function and adaptability in females by driving enhanced mitochondrial biogenesis and mitophagy. A second objective of this proposal will test if differences in bile acid (BA) metabolism provide protection against steatosis in females. Female rodents display chronically higher serum and fecal BA levels, paired with higher expression of hepatic genes controlling cholesterol/BA synthesis. Increasing rates of BA synthesis and fecal excretion via BA sequestrant drugs and chronic CYP7a1 overexpression also prevent and treat hepatic steatosis, suggesting a similar affect to what we see in female livers. Our preliminary data suggest that estrogen and exercise synergize to increase BA synthesis and fecal excretion only in females. We will test the hypothesis that trafficking of excess acetyl CoA away from de novo lipogenesis (synthesis of new fatty acids) and towards BA synthesis and fecal loss during postprandial conditions is an additional mechanism that protects females against hepatic steatosis. Overall, this proposal will examine if hepatic ERα signaling is obligatory for sex differences in hepatic mitochondrial function and BA metabolism and if these factors independently impact risk for hepatic steatosis in female mice. We will test these questions by utilizing liver- specific ERα knockout mice (LERKO), exercise, surgical (ovariectomy), pharmacological (estradiol), and molecular (AAV for shRNA CYP7a1) approaches combined with novel in vivo metabolic tracing techniques, and direct measures of mitochondrial quality control and function. The overall objective of this proposal is to determine mechanistic interactions between estrogen, exercise, and mitochondrial function that drive risk for hepatic steatosis with a goal of determining therapeutic targets for female Veterans.

项目概要/摘要 肝脂肪变性（脂肪肝）是 2 型糖尿病、心血管疾病和进一步肝损伤的危险因素， 目前有 160 万女性退伍军人，预计这一数字将持续上升。 稳步增长使妇女的健康问题成为更年期之前的主要问题。 防止脂肪变性，但卵巢功能丧失和积累后风险急剧增加 有证据表明，雌激素信号传导的差异是主要调节因素。 健身也会增加肝脂肪变性和相关病理的风险。 体力活动和锻炼可以保护和治疗脂肪变性，即使是肥胖患者的肝脏异常。 线粒体功能对脂肪变性的病理学有很大贡献，并且可能是脂肪变性的主要目标 体力活动和锻炼可以缓解这种情况，但其机制仍然很大程度上未知。 雌激素可能是雌性啮齿类动物预防肝脂肪变性的原因，但雌激素的直接影响 我们最近的研究结果表明，雌激素信号对肝线粒体功能的影响很少受到关注。 雌性小鼠线粒体呼吸增加，活性氧 (H2O2) 排放减少， 与男性相比，在久坐的情况下可以预防脂肪变性。 呼吸能力对饮食和运动引起的代谢应激也更敏感，但这些 线粒体周转（生物发生和代谢）基因消融的小鼠的适应性特征部分减弱 这些数据形成了我们的假设，即增强女性线粒体功能对其至关重要。 针对脂肪变性的内在保护和对代谢应激的适应性反应我们将检验这一假设。 通过雌激素受体 α (ERα) 的雌激素信号传导对于肝线粒体升高是必需的 通过增强线粒体生物发生和线粒体自噬来增强女性的功能和适应性。 该提案的目的是测试胆汁酸（BA）代谢的差异是否可以提供保护 雌性啮齿类动物表现出长期较高的血清和粪便 BA 水平，同时也较高。 控制胆固醇/BA合成的肝脏基因的表达增加BA合成和粪便的速率。 通过 BA 螯合剂药物排泄和慢性 CYP7a1 过度表达也可预防和治疗肝病 脂肪变性，表明与我们在女性肝脏中看到的类似影响。我们的初步数据表明。 雌激素和运动协同作用，仅在女性中增加 BA 合成和粪便排泄。 假设从头脂肪生成（新脂肪酸的合成）中运输过量的乙酰辅酶A 餐后条件下的 BA 合成和粪便损失是另一种机制 总体而言，该提案将检查肝脏 ERα 信号传导是否有效。 肝线粒体功能和 BA 代谢的性别差异是必然的，如果这些因素 我们将利用肝脏来独立影响雌性小鼠肝脂肪变性的风险。 特异性 ERα 基因敲除小鼠 (LERKO)、运动、手术（卵巢切除术）、药物（雌二醇）和 分子（AAV for shRNA CYP7a1）方法与新颖的体内代谢追踪技术相结合， 线粒体质量控制和功能的直接测量 该提案的总体目标是 确定雌激素、运动和线粒体功能之间的机制相互作用，这些相互作用会导致风险 肝脂肪变性，旨在确定女性退伍军人的治疗目标。