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Critical Role for Hepatocyte-Specific eNOS in NAFLD and NASH
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posted on 2021-08-11, 14:14 authored by Rory P. Cunningham, Mary P. Moore, Ryan J. Daskek, Grace M. Meers, Takamune Takahashi, Ryan D. Sheldon, Andrew A. Wheeler, Alberto Diaz-Arias, Jamal A. Ibdah, Elizabeth J. Parks, John P. Thyfault, R. Scott RectorRegulation of endothelial nitric oxide
synthase (eNOS) in hepatocytes may be an important target in nonalcoholic fatty
liver disease (NAFLD) development and progression to steatohepatitis (NASH). In
this study, we show genetic deletion and viral knockdown of hepatocyte-specific
eNOS exacerbated hepatic steatosis and inflammation, decreased hepatic
mitochondrial fatty acid oxidation and respiration, increased mitochondrial H2O2
emission, and impaired the hepatic mitophagic (BNIP3 and LC3II) response.
Conversely, overexpressing eNOS in hepatocytes in vitro and in vivo increased
hepatocyte mitochondrial respiration and attenuated western diet induced NASH. Moreover, patients with elevated NAFLD
activity score (histology score of worsening steatosis, hepatocyte ballooning,
and inflammation) exhibited reduced hepatic eNOS expression which correlated
with reduced hepatic mitochondrial fatty acid oxidation and lower hepatic protein
expression of mitophagy protein BNIP3. The
current study reveals an important molecular role for hepatocyte-specific eNOS as a key
regulator of NAFLD/NASH susceptibility and mitochondrial quality control with
direct clinical correlation to patients with NASH.