A Potential Role of Nox1 Isoform of NADPH Oxidase in the Development of Nonalcoholic Steatohepatitis

Oxidative stress is known to play a critical role in the development of nonalcoholic steatohepatitis. To clarify the source of oxidative stress, we examined the expression of NADPH oxidase isoforms in the liver of high fat diet (HFD)-fed mice. The mRNA expression of Nox1, but not of Nox2 or Nox4 was significantly elevated after 8 weeks of HFD. Increased levels of serum alanine aminotransferase and hepatic cleaved caspase-3 in HFD-fed wild-type mice (WT) were significantly ameliorated in mice deficient in Nox1 (Nox1-KO). Increased nitrotyrosine adduct formation was observed in hepatic sinusoids of WT, which was significantly suppressed in Nox1-KO. The expression of Nox1 mRNA was much higher in the fractions of liver sinusoidal endothelial cells (LSECs) than in those of hepatocytes. In primary cultured LSECs, palmitic acid, a saturated free fatty acid, significantly up-regulated Nox1 mRNA. Accordingly, Nox1 in sinusoidal endothelial cells may be one of the sources of oxidative stress in the liver to promote peroxinitrite-induced hepatocellular injury.