Aerobic Fitness, Mitochondrial Function, and Fatty Liver Disease.

有氧健身、线粒体功能和脂肪肝。

基本信息

批准号：
10205054
负责人：
John P Thyfault
金额：
$ 46.6万
依托单位：
UNIVERSITY OF KANSAS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-01 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10205054
关键词：
Acetyl Coenzyme A Acetylation Acute Aerobic Aerobic Exercise Bile Acid Biosynthesis Pathway Bile Acids Biochemical Cholesterol Chronic Citrates Citric Acid Cycle Clinical Coenzyme A Cytosol Data Development Epigenetic Process Event Excretory function Exercise Fatty Liver Fatty acid glycerol esters Feedback Gene Expression Genes Genetic Genetic Transcription Gluconeogenesis Goals Hepatic High Fat Diet Histone Acetylation Homeostasis Human Hyperglycemia Insulin Resistance Link Liver Liver Mitochondria Liver diseases Longevity Mediating Metabolic Metabolic Diseases Metabolic Pathway Mitochondria Mitochondrial Proteins Modeling Molecular Mus Non-Insulin-Dependent Diabetes Mellitus Nutrient Obesity Outcome Oxidative Stress Oxygen Pathologic Pathology Pathway interactions Pattern Pharmacology Phenotype Physical Endurance Physical Exercise Physical activity Play Predisposition Protein Acetylation Proteomics Rattus Role Running Sterols Sucrose Testing Tracer Training Transcriptional Activation Up-Regulation bile acid metabolism cholest-4-en-3-one cholesterol control endurance exercise epigenetic regulation feeding human subject improved in vivo lipid biosynthesis mitochondrial metabolism mortality risk novel overexpression oxidation respiratory response sedentary therapeutic target tool trafficking treadmill

项目摘要

Low aerobic capacity (AC) is a powerful predictor of early mortality and risk for metabolic disease including excessive hepatic fat storage (steatosis). Conversely, high AC is clinically associated with protection against hepatic steatosis and a healthier, longer lifespan even in the face of obesity. We will utilize a rat model selectively bred for divergent intrinsic AC (high or low running capacity [HCR/LCR]) to unravel mechanisms by which AC impacts hepatic steatosis and metabolic pathologies. In a sedentary condition, HCR rats have a 40% higher intrinsic AC and are protected against high fat/sucrose (HFD)-induced hepatic steatosis and insulin resistance while LCR are highly susceptible. We have shown that differences in hepatic mitochondrial function (MitoFX: defined here as fat oxidation, and respiratory capacity) between the HCR and LCR play an important role in their protection or susceptibility for hepatic steatosis, respectively. New data suggests that hepatic metabolic flux through TCA cycle and gluconeogenesis are also elevated in the HCR over the LCR rat, but these pathways have yet to be examined in the context of protection against steatosis. In addition, novel preliminary data suggests HCR rats have elevated bile acid (BA) synthesis paired with increased fecal sterol and BA excretion compared to LCR. Exercise trained mice which also have elevated MitoFX and are protected from steatosis show evidence of a similar upregulation of BA synthesis and excretion. We will test the hypothesis that increases in hepatic BA synthesis and fecal excretion is critical to the high AC and chronic exercise phenotype(s) and contributes to hepatic MitoFx, metabolic flux, and protection of steatosis by: 1) Pulling acetyl-CoA out of the mitochondria (minimizing feedback inhibition and mitochondrial protein acetylation) and 2) diverting acetyl-CoA away from accumulation and de-novo-lipogenesis (DNL) and towards BA synthesis and subsequent fecal loss via a “siphoning mechanism”. We will test these mechanisms utilizing pharmacological and molecular tools to modulate CYP7a1 activity and BA synthesis combined with in-vivo metabolic tracers in HCR/LCR rats and exercise vs. sedentary mice. Additionally, HCR livers display greater metabolic and transcriptional adaptability in response to high-fat diet (HFD) feeding than LCR. Our preliminary data suggests that enhanced transcriptional adaptability in the HCR livers is caused by increases in the acetylation of histones (H3K9ac and H3K27ac) that coordinate expression of genes involved in mitochondrial metabolism and specifically for BA synthesis. Thus, we posit that high AC and exercise induced increases in metabolic flux and enhanced BA synthesis likely increase acetyl CoA flux out of the mitochondria and into the cytosol where it can serve as a substrate for histone acetylation. This proposal will also test the hypothesis that livers from HCR rats and from exercised mice can transcriptionally adapt to high fat diets and avoid steatosis through a relationship linking hepatic MitoFX, BA synthesis and excretion, and epigenetic mechanisms (histone acetylation).

低氧能力（AC）是早期死亡率和代谢疾病风险（包括过量肝脂肪储存（Steatosis））的有力预测指标。相反，高AC在临床上与肝脂肪变性的保护相关，即使面对肥胖，也更健康，更长的寿命。我们将使用大鼠模型选择性繁殖用于固有的AC（高或低运行能力[HCR/LCR]）来揭示AC影响肝脂肪变性和代谢病理的机制。在久坐的条件下，HCR大鼠的内在AC高40％，并受到高脂肪/蔗糖（HFD）诱导的肝脂肪变性和胰岛素耐药性的保护，而LCR高度易感。我们已经表明，HCR和LCR之间的肝脏线粒体功能（mitofx：在此定义为脂肪氧化和呼吸能力）的差异在其对肝脂肪变性的保护或易感性方面起着重要作用。新数据表明，通过LCR大鼠，HCR中通过TCA周期中的肝素代谢通量也升高，但在保护脂肪变性的情况下尚未检查这些途径。此外，新型的初步数据表明，HCR大鼠的胆汁酸（BA）合成升高，与粪便固醇增加和BA与LCR的极端比较配对。运动训练的小鼠也升高了mitofx并受到保护，免受脂肪变性，表明了BA合成和极端极端的上调的证据。我们将测试以下假设：肝ba合成和粪便排泄的增加对于高的AC和慢性运动表型至关重要乙酰辅酶A远离积累和脱诺沃 - 脂肪形成（DNL），并通过“虹吸机制”朝着BA合成以及随后的粪便损失。我们将利用药物和分子工具来测试这些机制，以调节CYP7A1活性和BA合成，并结合HCR/LCR大鼠中的体内代谢示踪剂，运动与久坐小鼠相比。此外，与LCR相比，HCR生活对高脂饮食（HFD）的响应显示出更大的代谢和转录适应性。我们的初步数据表明，HCR寿命中的转录适应性增强是由组蛋白（H3K9AC和H3K27AC）的乙酰化增加引起的，该组蛋白（H3K9AC和H3K27AC）协调了参与线粒体代谢中涉及的基因的表达，并专门用于BA合成。这是我们提倡的，高交流和运动诱导的代谢通量增加并增强的BA合成可能会使乙酰基coA通量从线粒体中增加到细胞质中，并可以作为组蛋白乙酰化的底物。该提案还将检验以下假设：从HCR大鼠和行使的小鼠生命可以在转录上适应高脂饮食，并通过与肝细Mitofx，BA合成和排泄的关系以及表观遗传机制（组蛋白乙酰化）避免脂肪变性。