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.

建立改善肝脏组织学所需的运动益处和剂量机制 非酒精性脂肪性肝炎患者 项目摘要——在这个职业发展计划中，我将研究运动如何改善非酒精性 脂肪性肝炎 (NASH) 并回答有关运动 (1) 益处机制的三个非常重要的问题， (2)剂量，(3)对肝脏组织学的影响。该计划以我在 NASH 方面的临床经验为基础 指导培训：(1) 机械研究（Scot Kimball 博士），(2) 练习（Kathryn Schmitz、Christopher 博士） Sciamanna）和（3）NASH 试验（Rohit Loomba 博士）。该提案的中心假设是锻炼 训练将通过消耗肝糖原来激活 AMP 激活蛋白激酶 (AMPK)，从而导致肝 NASH 患者的脂肪减少和中间组织学终点改善。因为 糖原是运动过程中产生 ATP 的主要底物，我假设运动会产生糖原 与 AMPK 解离并随后激活 AMPK。中心假设基于 16 周的证明 对 18 名成年 NASH 患者进行的概念研究，其中我发现只有那些完成了 750 代谢测试的患者 任务当量（MET）-分钟/周的运动剂量达到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) 测量肝脏脂肪，替代 组织学反应。我观察到这一点与 AMPK 通路的间接变化同时发生，表明 AMPK 是通过运动激活的。虽然我没有研究 >750 MET-min/wk 的运动剂量，但更高的剂量似乎是合理的 可能更有效，因为糖原消耗需要持续的中等强度 锻炼。根据这些试点数据，我将进行一项为期 16 周的临床试验，并将患有 NASH 的成人随机分配到不同的组 运动剂量（750 或 1,000 MET-min/周）或标准临床护理。为了确保坚持，每次练习 会议将在亲自或远程远程医疗的直接监督下完成，然后 立即计算运动剂量，即强度 (MET) x 频率（一次）x 时间（分钟）。在目标 1 中，我 将通过磁共振波谱测量肝糖原的变化来研究运动益处的机制 单次持续中等强度运动后的 ATP。在目标 2 中，我将辨别哪个剂量是 经过 16 周的运动训练后，对于减少 MRI-PDFF 最为有效。在目标 3 中，我将衡量重要的 中间组织学终点（NASH 活动评分）和机制（AMPK 激活、AMPK 目标）。共同 肝组织中糖原与 AMPK 结合的定位将用于确认间接 MR 波谱证据 来自目标 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潜在机制 端点，包括 NASH 活动。这项研究将通过生成样本数据为未来的试验设计提供信息 研究运动对长期组织学结果（包括肝纤维化）影响所需的大小估计。我 我致力于成为一名医师科学家，并制定了我的培训计划以实现科学目标 独立并为推进 NASH 和公共卫生研究做出重大贡献。