Journal
AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM
Volume 317, Issue 4, Pages E605-E616Publisher
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpendo.00096.2019
Keywords
endothelial nitric oxide synthase; mitophagy; NAFLD; steatohepatitis
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Funding
- Veterans Affaris Merit Grant [I01BX003271]
- National Institute of Diabetes and Digestive and Kidney Diseases [DK-088940]
- American Heart Association [14POST20110034]
- University of Missouri Department of Medicine Research Council Grant
- Missouri Foundation for Medical Research
- Richard Wallace Foundation
- Veterans Affairs Merit Grant [I01 RX000123]
- Harry S Truman Memorial Veterans Hospital in Columbia, MO
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Dysregulated mitochondrial quality control leads to mitochondrial functional impairments that are central to the development and progression of hepatic steatosis to nonalcoholic steatohepatitis (NASH). Here, we identify hepatocellular localized endothelial nitric oxide synthase (eNOS) as a novel master regulator of mitochondrial quality control. Mice lacking eNOS were more susceptible to Western diet-induced hepatic inflammation and fibrosis in conjunction with decreased markers of mitochondrial biogenesis and turnover. The hepatocyte-specific influence was verified via magnetic activated cell sorting purified primary hepatocytes and in vitro siRNA-induced knockdown of eNOS. Hepatic mitochondria from eNOS knockout mice revealed decreased markers of mitochondrial biogenesis (PPAR gamma coactivator-1 alpha, mitochondrial transcription factor A) and autophagy/mitophagy [BCL-2-interacting protein-3 (BNIP3), 1A/1B light chain 3B (LC3)]. suggesting decreased mitochondrial turnover rate. eNOS knockout in primary hepatocytes exhibited reduced fatty acid oxidation capacity and were unable to mount a normal BNIP3 response to a mitophagic challenge compared with wild-type mice. Finally, we demonstrate that eNOS is required in primary hepatocytes to induce activation of the stress-responsive transcription factor nuclear factor erythroid 2-related factor 2 (NRF2). Thus, our data demonstrate that eNOS is an important regulator of hepatic mitochondrial content and function and NASH susceptibility.
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