Establishing the mechanism of benefit and dose of exercise required to improve liver histology in patients with nonalcoholic steatohepatitis

建立改善非酒精性脂肪性肝炎患者肝脏组织学所需的运动益处和剂量机制

• 批准号: 10548186
• 负责人: Jonathan G Stine
• 金额: $ 20.01万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-01 至 2026-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10548186
• 关键词: 5' -AMP-activated protein kinase; Acute; Adherence; Adult; Animal Disease Models; Binding; Chronic; Clinical; Clinical Trials; Data; Development; Disease; Disease Progression; Dissociation; Dose; Enrollment; Ensure; Exercise; Fatty acid glycerol esters; Frequencies; Future; Glycogen; Goals; Hepatic; Histologic; Histology; Intervention Trial; Liver; Liver Fibrosis; Liver Glycogen; Liver diseases; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Measures; Mentors; Metabolic; Metabolic Pathway; Outcome; Pathogenesis; Pathway interactions; Patients; Persons; Pharmacotherapy; Physical activity; Physicians; Program Development; Protons; Public Health; Randomized; Recommendation; Research; Sample Size; Scientist; Strenuous Exercise; Supervision; Testing; Time; Tissues; Training; Variant; career; career development; chronic liver disease; clinical care; density; design; effective therapy; exercise intensity; exercise prescription; exercise program; exercise training; experience; fatty acid oxidation; improved; innovation; lipid biosynthesis; liver biopsy; liver transplantation; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; oxidation; prevent; programs; randomized, clinical trials; response; standard of care; telehealth; trial design; vigorous intensity

Establishing the mechanism of benefit and dose of exercise required to improve liver histology in patients with nonalcoholic steatohepatitis PROJECT SUMMARY— In this career development program, I will study how exercise improves nonalcoholic steatohepatitis (NASH) and answer three highly significant questions about exercise’s (1) mechanism of benefit, (2) dose, and (3) impact on liver histology. This program builds on my clinical experience in NASH through mentored training in: (1) mechanistic study (Dr. Scot Kimball), (2) exercise (Drs. Kathryn Schmitz, Christopher Sciamanna), and (3) NASH trials (Dr. Rohit Loomba). The central hypothesis of this proposal is that exercise training will activate AMP-activated protein kinase (AMPK) by depleting liver glycogen, leading to liver fat reduction and intermediate histologic endpoint improvement in patients with NASH. Because glycogen is the main substrate used during exercise to generate ATP, I hypothesize exercise will lead to glycogen dissociation from AMPK and subsequent AMPK activation. The central hypothesis is based on a 16-wk proof of concept study in 18 adult patients with NASH in which I found only those who completed a 750 Metabolic Equivalents of Task (MET)-min/wk dose of exercise achieved the minimal clinically important difference in magnetic resonance imaging proton density fat fraction (MRI-PDFF) measured liver fat, that surrogates for histologic response. I observed this in parallel with indirect changes in the AMPK pathway, suggesting AMPK was activated by exercise. While I did not study exercise dose >750 MET-min/wk, it is plausible that higher doses may be even more effective because glycogen depletion requires sustained moderate-vigorous intensity exercise. Given these pilot data, I will conduct a 16-wk clinical trial and randomize adults with NASH to different exercise doses (750 or 1,000 MET-min/wk) or standard clinical care. To ensure adherence, each exercise session will be completed under direct supervision, either in-person or remotely with telehealth, followed by immediate calculation of exercise dose as intensity (METs) x frequency (one session) x time (min). In Aim 1, I will study the mechanism of exercise’s benefit with MR-spectroscopy measured change in liver glycogen and ATP following a single session of sustained moderate-vigorous exercise. In Aim 2, I will discern which dose is most effective in reducing MRI-PDFF after 16-wks of exercise training. In Aim 3, I will measure important intermediate histologic endpoints (NASH activity score) and mechanisms (AMPK activation, AMPK targets). Co- localization of glycogen binding to AMPK in liver tissue will be used to confirm indirect MR-spectroscopy evidence from Aim 1. When I am successful, I will have provided rigorous evidence to decipher the dose required and the underlying mechanisms explaining how exercise training leads to improvement in intermediate histologic endpoints, including NASH activity. This research will inform future trial design by generating data for sample size estimates necessary to study exercise’s impact on long-term histologic outcomes, including liver fibrosis. I am committed to a career as a physician scientist and have constructed my training plan to achieve scientific independence and make substantial contributions to advancing the study of NASH and public health.

建立改善肝组织学所需的益处和运动剂量的机制 非酒精性脂肪性肝炎的患者 项目摘要 - 在此职业发展计划中，我将研究运动如何改善非酒精性 脂肪性肝炎（NASH），回答有关运动的三个高度重大问题（1）福利机制， （2）剂量，（3）对肝组织学的影响。这个程序以我在纳什的临床经验为基础 指导培训：（1）机械研究（Scot Kimball博士），（2）练习（凯瑟琳·施密茨（Kathryn Schmitz）博士，克里斯托弗 SCIAMANNA）和（3）NASH试验（Rohit Loomba博士）。该提议的中心假设是练习 训练将通过耗尽肝糖原来激活AMP激活的蛋白激酶（AMPK），导致肝脏 NASH患者的脂肪减少和中间组织学终点改善。因为 糖原是运动过程中用于生成ATP的主要底物，我假设运动会导致糖原 与AMPK分离和随后的AMPK激活。中心假设基于16周的证明 在18例NASH患者中，我发现那些完成750代谢的人的概念研究 任务（MET） - 分钟/WK锻炼的等效物在临床上取得了最小的临床重要差异 磁共振成像质子密度脂肪分数（MRI-PDFF）测量的肝脂肪，替代 组织学反应。我与AMPK途径的间接变化并行观察到了这一点，这表明AMPK 虽然我没有学习运动剂量> 750 met-min/wk，但更高剂量是合理的 可能会更有效，因为糖原的部署需要持续的现代强度 锻炼。鉴于这些试验数据，我将进行16周的临床试验，并将NASH的成年人随机分配给不同 运动剂量（750或1,000 MET/WK）或标准临床护理。为了确保依从性，每次练习 会议将在直接监督下完成，无论是与远程医疗的远程监督，其次是 立即计算运动剂量为强度（MetS）X频率（一个会话）x时间（最小）。在AIM 1中，我 将研究锻炼方法通过MR谱镜检查的机理，测量了肝糖原和 在一次持续的现代剧烈运动之后，ATP。在AIM 2中，我会发现哪种剂量是 经过16周的运动训练，最有效地减少MRI-PDFF。在AIM 3中，我将衡量重要 中间组织学终点（NASH活性评分）和机制（AMPK激活，AMPK目标）。共同 糖原与AMPK结合在肝组织中的定位将用于确认间接的MR谱镜证据 从目标1。当我成功时，我将提供严格的证据来破译所需的剂量和 解释运动训练如何导致中间组织学改善的基本机制 终点，包括NASH活动。这项研究将通过生成样本数据来为未来的试验设计提供信息 研究运动对长期组织学结局的影响所需的尺寸估计值，包括肝纤维化。我 致力于从事物理科学家的职业，并制定了我的培训计划以实现科学 独立性并为推进纳什和公共卫生的研究做出了重大贡献。