Jonathan G Stine1,2,3,4, Dandan Xu5, Kathryn Schmitz6,7,8,9, Christopher Sciamanna6,7,10, Scot R Kimball5. 1. Division of Gastroenterology and Hepatology, Department of Medicine, The Pennsylvania State University- Milton S. Hershey Medical Center, 500 University Drive, Hershey, PA, 17033, USA. jstine@pennstatehealth.psu.edu. 2. Department of Public Health Sciences, The Pennsylvania State University- Milton S. Hershey Medical Center, Hershey, PA, USA. jstine@pennstatehealth.psu.edu. 3. Liver Center, The Pennsylvania State University- Milton S. Hershey Medical Center, Hershey, PA, USA. jstine@pennstatehealth.psu.edu. 4. Cancer Institute, The Pennsylvania State University- Milton S. Hershey Medical Center, Hershey, PA, USA. jstine@pennstatehealth.psu.edu. 5. Department of Cellular and Molecular Physiology, The Pennsylvania State University- College of Medicine, Hershey, PA, USA. 6. Department of Public Health Sciences, The Pennsylvania State University- Milton S. Hershey Medical Center, Hershey, PA, USA. 7. Cancer Institute, The Pennsylvania State University- Milton S. Hershey Medical Center, Hershey, PA, USA. 8. Department of Kinesiology, The Pennsylvania State University- College of Medicine, Hershey, PA, USA. 9. Department of Physical Medicine and Rehabilitation, The Pennsylvania State University- Milton S. Hershey Medical Center, Hershey, PA, USA. 10. Department of Medicine, The Pennsylvania State University- Milton S. Hershey Medical Center, Hershey, PA, USA.
Abstract
INTRODUCTION: Nonalcoholic fatty liver disease (NAFLD) is the leading cause of liver disease worldwide. Nonalcoholic steatohepatitis (NASH), is a more severe type of NAFLD. Exercise improves NASH, by reversing steatosis, and may arrest fibrosis. However, the mechanisms underlying these interactions are unknown. AMP-activated protein kinase (AMPK) is a fuel-sensing enzyme that is activated by energy stress. Mammalian target of rapamycin in complex 1 (mTORC1) is a nutrient sensor that regulates protein synthesis. In NASH, AMPK activity is low and mTORC1 is high. In healthy persons, exercise activates AMPK and suppresses mTORC1. We examined the effects of exercise on hepatic ribosomal protein S6 phosphorylation, a downstream target of AMPK and mTORC1 in patients with NASH. METHODS: Three subjects with biopsy-proven NASH underwent a structured, 20-week aerobic exercise intervention, five-days a week for 30-min at a moderate intensity (40-55% of VO2max). Immunofluorescence staining for rpS6 phosphorylation in hepatic tissue was quantified by ImageJ software. RESULTS: Following 20-weeks of aerobic exercise, rpS6 levels were significantly attenuated (3.9 ± 1.9 pre-exercise vs. 1.4 +/0.4 post-exercise, p = 0.04). CONCLUSIONS: These findings suggest exercise modulates the AMPK/mTORC1 pathway in patients with NASH and may guide the design of future studies into the mechanism of how exercise improves NASH and possibly reverses fibrosis.
INTRODUCTION:Nonalcoholic fatty liver disease (NAFLD) is the leading cause of liver disease worldwide. Nonalcoholic steatohepatitis (NASH), is a more severe type of NAFLD. Exercise improves NASH, by reversing steatosis, and may arrest fibrosis. However, the mechanisms underlying these interactions are unknown. AMP-activated protein kinase (AMPK) is a fuel-sensing enzyme that is activated by energy stress. Mammalian target of rapamycin in complex 1 (mTORC1) is a nutrient sensor that regulates protein synthesis. In NASH, AMPK activity is low and mTORC1 is high. In healthy persons, exercise activates AMPK and suppresses mTORC1. We examined the effects of exercise on hepatic ribosomal protein S6 phosphorylation, a downstream target of AMPK and mTORC1 in patients with NASH. METHODS: Three subjects with biopsy-proven NASH underwent a structured, 20-week aerobic exercise intervention, five-days a week for 30-min at a moderate intensity (40-55% of VO2max). Immunofluorescence staining for rpS6 phosphorylation in hepatic tissue was quantified by ImageJ software. RESULTS: Following 20-weeks of aerobic exercise, rpS6 levels were significantly attenuated (3.9 ± 1.9 pre-exercise vs. 1.4 +/0.4 post-exercise, p = 0.04). CONCLUSIONS: These findings suggest exercise modulates the AMPK/mTORC1 pathway in patients with NASH and may guide the design of future studies into the mechanism of how exercise improves NASH and possibly reverses fibrosis.
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