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: 10516037
• 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/10516037
• 关键词: Ablation; Acetyl Coenzyme A; Aerobic Exercise; Affect; Attention; Automobile Driving; Bile Acid Biosynthesis Pathway; Bile Acids; Biogenesis; Cardiovascular Diseases; Chronic; Cirrhosis; Clinical Data; Data; Diet; Enzymes; Estradiol; Estrogen Receptor alpha; Estrogen decline; 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; Membrane Potentials; Menopause; Metabolic; Metabolic stress; Mitochondria; Molecular; Mus; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Operative Surgical Procedures; Ovarian; Ovariectomy; Pathology; Patients; Pharmaceutical Preparations; Physical Exercise; Physical activity; 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; bile acid metabolism; cardiovascular risk factor; cholesterol control; diet and exercise; fitness; in vivo; lipid biosynthesis; liver injury; male; men; military veteran; non-alcoholic fatty liver; normal aging; novel; obese patients; overexpression; oxidation; pharmacologic; physical inactivity; prevent; respiratory; response; sedentary; sex; sexual dimorphism; small hairpin RNA; synergism; 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.

项目总结/摘要 肝脏脂肪变性（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， 退伍军人的所有主要健康问题。目前有160万名女退伍军人，预计这一数字将在2010年达到100万。 稳步增长，使妇女健康问题成为今后的一个主要关切。在更年期之前，女性 防止脂肪变性，但风险急剧增加后，卵巢功能丧失和积累 有证据表明雌激素信号传导的差异是主要的介质。缺乏身体活动和低 健身也会增加肝脂肪变性和相关病理的风险。相比之下， 体力活动和锻炼可以保护和治疗脂肪变性，即使在肥胖患者中也是如此。阿贝伐他汀 线粒体功能对脂肪变性的病理学有很大贡献，并且很可能是脂肪变性的主要靶点。 身体活动和锻炼的影响，以减轻病情，但机制仍然在很大程度上未知。 雌激素可能是保护雌性啮齿类动物免受肝脂肪变性的原因，但雌激素的直接作用可能是保护雌性啮齿类动物免受肝脂肪变性的原因。 雌激素信号对肝线粒体功能的影响很少受到关注。我们最近的研究结果表明， 雌性小鼠显示线粒体呼吸增加，活性氧（H2 O2）排放降低， 与男性相比，在久坐状态下可以防止脂肪变性。雌性肝线粒体 呼吸能力对饮食和运动引起的代谢应激也更敏感，但这些 在线粒体转换基因消除的小鼠中，适应性特征部分减弱（生物发生和 线粒体自噬）。这些数据形成了我们的假设，即女性线粒体功能的增强对她们的发育至关重要。 对脂肪变性的内在保护和对代谢应激的适应性反应。我们将检验这个假设 通过雌激素受体α（ERα）的雌激素信号传导是肝线粒体 通过驱动增强的线粒体生物合成和线粒体自噬来增强女性的功能和适应性。第二 本提案的目的是测试胆汁酸（BA）代谢的差异是否提供了针对以下疾病的保护： 女性脂肪变性。雌性啮齿动物显示长期较高的血清和粪便BA水平，与较高的 控制胆固醇/BA合成的肝基因的表达。增加BA合成率和粪便 通过BA螯合剂药物的排泄和慢性CYP 7a 1过表达也可以预防和治疗肝细胞癌。 脂肪变性，这与我们在女性肝脏中看到的相似。我们的初步数据显示， 雌激素和运动协同作用仅在雌性中增加BA合成和粪便排泄。我们将测试 假设过量乙酰辅酶A从从头脂肪生成（新脂肪酸合成）中转运 并且在餐后条件下朝向BA合成和粪便损失是另外的机制， 保护女性免受肝脂肪变性。总的来说，这项建议将检查肝脏ERα信号传导是否是 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 独立影响雌性小鼠肝脂肪变性的风险。我们将用肝脏来测试这些问题- 特异性ERα敲除小鼠（LERKO）、运动、手术（卵巢切除术）、药理学（雌二醇）和 分子（AAV用于shRNA CYP 7a 1）方法与新的体内代谢追踪技术相结合， 以及线粒体质量控制和功能的直接测量。本建议的总体目标是 确定雌激素、运动和线粒体功能之间的机械相互作用，这些相互作用会导致糖尿病风险 肝脂肪变性，目的是确定女性退伍军人的治疗目标。

项目成果

Timing and intensity of exercise for glucose control. Reply to Chacko E. [letter].

控制血糖的运动时间和强度。

• DOI: 10.1007/s00125-014-3359-9
• 发表时间: 2014
• 期刊: Diabetologia
• 影响因子: 8.2
• 作者: Booth,FrankW;Thyfault,JohnP
• 通讯作者: Thyfault,JohnP

Effects of ovariectomy and intrinsic aerobic capacity on tissue-specific insulin sensitivity.

卵巢切除术和内在有氧能力对组织特异性胰岛素敏感性的影响。

• DOI: 10.1152/ajpendo.00434.2015
• 发表时间: 2016
• 期刊: American journal of physiology. Endocrinology and metabolism
• 作者: Park,Young-Min;Rector,RScott;Thyfault,JohnP;Zidon,TereseM;Padilla,Jaume;Welly,RebeccaJ;Meers,GraceM;Morris,MatthewE;Britton,StevenL;Koch,LaurenG;Booth,FrankW;Kanaley,JillA;Vieira-Potter,VictoriaJ
• 通讯作者: Vieira-Potter,VictoriaJ

Soy compared with milk protein in a Western diet changes fecal microbiota and decreases hepatic steatosis in obese OLETF rats.

• DOI: 10.1016/j.jnutbio.2017.05.004
• 发表时间: 2017-08
• 期刊: The Journal of nutritional biochemistry
• 作者: Panasevich MR;Schuster CM;Phillips KE;Meers GM;Chintapalli SV;Wankhade UD;Shankar K;Butteiger DN;Krul ES;Thyfault JP;Rector RS
• 通讯作者: Rector RS

Anti-inflammatory effects of exercise training in adipose tissue do not require FGF21.

• DOI: 10.1530/joe-17-0190
• 发表时间: 2017-11
• 期刊: The Journal of endocrinology
• 作者: Porter JW;Rowles JL 3rd;Fletcher JA;Zidon TM;Winn NC;McCabe LT;Park YM;Perfield JW 2nd;Thyfault JP;Rector RS;Padilla J;Vieira-Potter VJ
• 通讯作者: Vieira-Potter VJ

AMPK agonist AICAR delays the initial decline in lifetime-apex V̇o2 peak, while voluntary wheel running fails to delay its initial decline in female rats.

• DOI: 10.1152/physiolgenomics.00078.2015
• 发表时间: 2016-02
• 期刊: Physiological genomics
• 影响因子: 4.6
• 作者: Ryan G. Toedebusch;Gregory N Ruegsegger;Joshua F. Braselton;Alexander J. Heese;John C Hofheins;T. Childs;J. Thyfault;F. Booth