Exercise, mitochondrial function, and fatty acid oxidation in fatty liver disease

描述（由申请人提供）：据估计，非酒精性脂肪肝（NAFLD）影响1/3的美国成年人口。在这种高脂环境中，肝线粒体和过氧化物酶体被认为协同工作以防止脂质积聚;然而，增强的过氧化物酶体活性产生活性氧（ROS），并可能对肝细胞具有损伤作用。运动被认为是NAFLD的最佳治疗方法之一，但对其益处的分子解释很少。我们开发了一种线粒体三功能蛋白（催化β-氧化的最后3个步骤）杂合小鼠（MTPa），其由于线粒体脂肪酸氧化受损和长链脂肪酸代谢产物积累而发生NAFLD和胰岛素抵抗。该建议的中心假设是，日常锻炼增加MTPa小鼠的肝线粒体生物合成，导致线粒体脂肪酸氧化能力增加，并通过过氧化物酶体途径减少脂肪酸的运输，最终减少肝氧化应激，脂肪变性和肝损伤。我们还推测，这种降低的肝脏氧化应激将改善肝脏胰岛素信号传导和全身胰岛素敏感性。MTP和MTP小鼠将自愿在跑步轮上运动或保持久坐6个月。将评估肝线粒体生物发生和过氧化物酶体增殖和脂肪酸氧化能力的测量，沿着肝脂质过氧化和氧化应激。MTP小鼠还将经历高胰岛素-正常血糖钳夹以评估运动对肝脏胰岛素信号传导和全身胰岛素敏感性的影响。该项目的长期目标是探索与运动训练降低肝脂肪变性严重程度相关的机制。公共卫生相关性：据估计，超过1000万美国人患有线粒体脂肪酸氧化障碍，9000万美国成年人患有NAFLD。不幸的是，目前治疗的有效性和生物学机制在很大程度上是未知的。本项目的重点是确定运动通过增加肝脏线粒体功能、减少肝损伤和改善肝脏胰岛素敏感性来降低NAFLD发生率的潜在机制和治疗靶点。

DESCRIPTION (provided by applicant): Nonalcoholic fatty liver disease (NAFLD) is estimated to affect 1/3 of the US adult population. In this high-fat environment, hepatic mitochondria and peroxisomes are thought to work in concert to prevent lipid accumulation; however, enhanced peroxisomal activity generates reactive oxygen species (ROS) and may have damaging effects on hepatocytes. Exercise is considered among the best treatments for NAFLD, but there is little molecular explanation for its benefits. We have developed a mitochondrial trifunctional protein (catalyzes last 3 steps in beta-oxidation) heterozygous mouse (MTPa) that develops NAFLD and insulin resistance due to impairment in mitochondrial fatty acid oxidation and accumulation of long chain fatty acid metabolites. The central hypothesis of this proposal is that daily exercise increases hepatic mitochondrial biogenesis in MTPa mice resulting in increased mitochondrial fatty acid oxidative capacity and reduced trafficking of fatty acids through peroxisomal pathways culminating in reduced hepatic-oxidative stress, -steatosis, and liver injury. We also postulate that this reduced hepatic oxidative stress will improve hepatic insulin signaling and whole body insulin sensitivity. MTP and MTP mice will either voluntarily exercise on running wheels or remain sedentary for 6 months. Measures of hepatic mitochondrial biogenesis and peroxisomal proliferation and fatty acid oxidative capacity will be assessed, along with hepatic lipid peroxidation and oxidative stress. MTP mice also will undergo hyperinsulinemic-euglycemic clamps to assess the influence of exercise on hepatic insulin signaling and whole-body insulin sensitivity. The long-term goal of this project is to explore mechanisms linked to reduced severity of hepatic steatosis with exercise training. PUBLIC HEALTH RELEVANCE: It also is estimated that more than 10 million Americans have disorders in mitochondrial fatty acid oxidation and 90 million US adults have NAFLD. Unfortunately, the effectiveness and biological mechanisms of current treatments are largely unknown. It is the focus of this project to identify potential mechanisms and therapeutic targets by which exercise can reduce the incidence of NAFLD by increasing hepatic mitochondrial function, reduce liver injury, and improve hepatic insulin sensitivity.