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.

项目摘要/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的肝损伤的危险因素， 退伍军人的所有主要健康问题。目前有160万女退伍军人，预计 稳步使妇女的健康问题成为主要问题。更年期之前，女性是 防止脂肪变性，但卵巢功能丧失并积累后，风险大大增加 有证据表明，雌激素信号传导的差异是主要中介体。身体不活跃和低 健身还可以增加肝脂肪变性和相关病理的风险。相反，增加 即使在肥胖患者中，体育锻炼和运动也可以保护和治疗脂肪变性。肝脏异常 线粒体功能对脂肪变性的病理有很大贡献，很可能是 体育锻炼和锻炼以减轻状况的影响，但机制基本未知。 雌激素可能是雌性啮齿动物中肝脏脂肪变性的保护原因 肝脏线粒体功能上的雌激素信号传导很少受到关注。我们最近的发现表明 雌性小鼠的线粒体呼吸增加，活性氧（H2O2）发射较低，并且 与雄性相比，在久坐状况下对脂肪变性的保护。雌性肝线粒体 呼吸能力对饮食和运动引起的代谢压力也更敏感，但是这些 在有线粒体周转的遗传消融的小鼠中，自适应性状部分减少（生物发生和 线粒体）。这些数据构成了我们的假设，即增强女性的线粒体功能对她们 对脂肪变性的固有保护和对代谢压力的适应性反应。我们将检验假设 通过高架线粒体的高架信号传导 通过驱动增强的线粒体生物发生和线粒体的功能和适应能力。第二 该提案的目的将测试胆汁酸（BA）代谢是否提供保护 女性的脂肪变性。雌性啮齿动物表现出长期更高的血清和粪便BA水平，与更高 控制胆固醇/BA合成的肝基因的表达。 BA合成和粪便的速率提高 通过BA螯合药物和慢性CYP7A1过表达排泄也预防和治疗肝 脂肪变性，表明与我们在女性生活中看到的相似。我们的初步数据表明 雌激素和运动协同作用以增加女性的BA合成和粪便排泄。我们将测试 假设过多的乙酰基CoA从头脂肪生成（合成新脂肪酸） 在餐后条件期间朝着BA合成和粪便损失是一种附加机制 保护女性免受肝脂肪变性。总体而言，该建议将检查肝ERα信号是否是 肝线粒体功能和BA代谢的性别差异的强制性差异以及这些因素 独立影响雌性小鼠肝脂肪变性的风险。我们将使用肝脏测试这些问题 - 特定的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（用于shRNA CYP7A1的AAV）方法与新型体内代谢追踪技术相结合， 并直接衡量线粒体质量控制和功能。该提议的总体目的是 确定雌激素，运动和线粒体功能之间的机械相互作用，以驱动风险 肝脂肪变性的目的是确定女性退伍军人的治疗靶标。