Hepatocyte-specific eNOS deletion impairs exercise-induced adaptations in hepatic mitochondrial function and autophagy

Details

• Alternative Title:
  Obesity (Silver Spring)
• Personal Author:
  Cunningham, Rory P. ; Moore, Mary P. ; Dashek, Ryan J. ; Meers, Grace M. ; Jepkemoi, Vivien ; Takahashi, Takamune ; Vieira-Potter, Victoria J. ; Kanaley, Jill A. ; Booth, Frank W. ; Rector, R. Scott
• Description:
  Objective:
  
  Endothelial nitric oxide synthase (eNOS) is a potential mediator of exercise-induced hepatic mitochondrial adaptations.
  
  Methods:
  
  Here, male and female hepatocyte-specific eNOS knockout (eNOShep−/−) and intact hepatic eNOS (eNOSfl/fl) mice performed voluntary wheel running exercise (EX) or remained in sedentary cage conditions for 10 weeks.
  
  Results:
  
  EX resolved the exacerbated hepatic steatosis in eNOShep−/− male mice. Elevated H2O2 emission (~50% higher in eNOShep−/− vs eNOSfl/fl mice) was completely ablated with EX. Interestingly, EX increased [1-14C] palmitate oxidation in male eNOSfl/fl, but this was blunted in the eNOShep−/− male mice. eNOShep−/− mice had lower markers of the energy sensors pAMPK/AMPK and mTOR and p-mTOR, and the autophagy initiators ULK1 and pULK1 compared to eNOSfl/fl mice. Females showed elevated ETC protein content and markers of mitochondrial biogenesis (TFAM, pgc1α).
  
  Conclusions:
  
  Collectively, we demonstrate for the first time the requirement of eNOS in hepatocytes in the EX-induced increases in hepatic fatty acid oxidation in male mice. Deletion of eNOS in hepatocytes also appears to impair the energy sensing ability of the cell and inhibit the activation of the autophagy initiating factor ULK1. These data uncover the important and novel role of hepatocyte eNOS in exercise-induced hepatic mitochondrial adaptations.
  
  
• Subjects:
  AMP-Activated Protein Kinases Animals Article Autophagy ENOS Exercise Female Hepatocytes Male Mammals Mice Mice, Inbred C57BL Mice, Knockout Mitochondria NAFLD Nitric Oxide Synthase Type III Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha TOR Serine-Threonine Kinases

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• Source:
  Obesity (Silver Spring). 30(5):1066-1078
• Pubmed ID:
  35357089
• Pubmed Central ID:
  PMC9050943
• Document Type:
  Journal Article
• Funding:
  T32 OD011126/OD/NIH HHSUnited States/ ; T32 OD011126/CD/ODCDC CDC HHSUnited States/ ; I01 BX003271/BX/BLRD VAUnited States/ ; 18-00754/American College of Sports Medicine/ ; R01 DK113701/DK/NIDDK NIH HHSUnited States/ ; R01 DK113701-01/National Institute of Health/ ; I01BX003271/Veterans Affairs Merit Grant/
• Volume:
  30
• Issue:
  5
• Collection(s):
  CDC Public Access
• Main Document Checksum:
  urn:sha256:12e035f68a21d2c7b1cfb5925a14b1360513d8f19fbca7d08d20e93dcf6fa75b
• Download URL:
  https://stacks.cdc.gov/view/cdc/116884/cdc_116884_DS1.pdf
• File Type:
  [PDF - 2.31 MB ]