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

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.