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).

低有氧能力 (AC) 是早期死亡率和代谢疾病风险的有力预测因素，包括肝脏脂肪储存过多（离线脂肪变性），高 AC 在临床上与预防肝脂肪变性和健康、更长的寿命有关，即使面对肝脂肪变性也是如此。我们将利用针对不同的内在AC（高或低运行能力[HCR/LCR]）选择性培育的大鼠模型来揭示AC影响肝脂肪变性和代谢病理学的机制。在久坐的情况下，HCR 大鼠的内在 AC 升高 40%，并且可以免受高脂肪/蔗糖 (HFD) 诱导的肝脂肪变性和胰岛素抵抗，而 LCR 则非常容易受到肝线粒体功能差异的影响（MitoFX：此处定义）。新数据表明肝脏代谢通量与 LCR 大鼠相比，HCR 中的 TCA 循环和糖异生也有所增加，但这些途径尚未在防止脂肪变性的背景下进行检查。此外，新的初步数据表明 HCR 大鼠的胆汁酸 (BA) 合成也有所增加。与 LCR 相比，经过运动训练的小鼠的 MitoFX 水平升高并且免受脂肪变性，显示出类似的 BA 和排泄上调的综合证据。肝脏 BA 合成和粪便排泄对于高 AC 和慢性运动表型至关重要，并通过以下方式促进肝脏 MitoFx、代谢通量和脂肪变性保护： 1) 将乙酰辅酶 A 从线粒体中拉出（最大限度地减少反馈抑制和线粒体蛋白质乙酰化）和2）将乙酰辅酶A从积累和从头脂肪生成（DNL）转移到BA合成和随后的粪便损失我们将利用药理学和分子工具结合体内代谢示踪剂来调节 CYP7a1 活性和 BA 合成，并在 HCR/LCR 大鼠和运动小鼠中测试这些机制。此外，HCR 肝脏表现出更强的代谢和代谢能力。我们的初步数据表明，HCR 肝脏中转录适应性的增强是由组蛋白乙酰化的增加引起的。（H3K9ac 和 H3K27ac）协调参与线粒体代谢、特别是 BA 合成的基因表达，因此，我们认为高 AC 和运动诱导的代谢通量增加和 BA 合成增强可能会增加乙酰辅酶 A 流出线粒体并进入线粒体的通量。该提案还将检验 HCR 大鼠和运动小鼠的肝脏可以通过转录适应高脂肪饮食并通过关系避免脂肪变性的假设。连接肝脏 MitoFX、BA 合成和排泄以及表观遗传机制（组蛋白乙酰化）。