The NOX1 isoform of NADPH oxidase is involved in dysfunction of liver sinusoids in nonalcoholic fatty liver disease

Misaki Matsumoto, Jia Zhang, Xueqing Zhang, Junjie Liu, Joy X. Jiang, Kanji Yamaguchi, Akiyuki Taruno, Masato Katsuyama, Kazumi Iwata, Masakazu Ibi, Wenhao Cui, Kuniharu Matsuno, Yoshinori Marunaka, Yoshito Itoh, Natalie J. Torok, Chihiro Yabe-Nishimura

Research output: Contribution to journalArticlepeer-review

32 Scopus citations


The increased production of reactive oxygen species (ROS) has been postulated to play a key role in the progression of nonalcoholic fatty liver disease (NAFLD). However, the source of ROS and mechanisms underlying the development of NAFLD have yet to be established. We observed a significant up-regulation of a minor isoform of NADPH oxidase, NOX1, in the liver of nonalcoholic steatohepatitis (NASH) patients as well as of mice fed a high-fat and high-cholesterol (HFC) diet for 8 weeks. In mice deficient in Nox1 (Nox1KO), increased levels of serum alanine aminotransferase and hepatic cleaved caspase-3 demonstrated in HFC diet-fed wild-type mice (WT) were significantly attenuated. Concomitantly, increased protein nitrotyrosine adducts, a marker of peroxynitrite-induced injury detected in hepatic sinusoids of WT, were significantly suppressed in Nox1KO. The expression of NOX1 mRNA was much higher in the fractions of enriched liver sinusoidal endothelial cells (LSECs) than in those of hepatocytes. In primary cultured LSECs, palmitic acid (PA) up-regulated the mRNA level of NOX1, but not of NOX2 or NOX4. The production of nitric oxide by LSECs was significantly attenuated by PA-treatment in WT but not in Nox1KO. When the in vitro relaxation of TWNT1, a cell line that originated from hepatic stellate cells, was assessed by the gel contraction assay, the relaxation of stellate cells induced by LSECs was attenuated by PA treatment. In contrast, the relaxation effect of LSECs was preserved in cells isolated from Nox1KO. Taken together, the up-regulation of NOX1 in LSECs may elicit peroxynitrite-mediated cellular injury and impaired hepatic microcirculation through the reduced bioavailability of nitric oxide. ROS derived from NOX1 may therefore constitute a critical component in the progression of NAFLD.

Original languageEnglish (US)
Pages (from-to)412-420
Number of pages9
JournalFree Radical Biology and Medicine
StatePublished - Feb 1 2018


  • Liver sinusoidal endothelial cells (LSECs)
  • Nitric oxide (NO)
  • Nitrotyrosine
  • Nonalcoholic fatty liver disease (NAFLD)
  • Reactive oxygen species (ROS)

ASJC Scopus subject areas

  • Biochemistry
  • Physiology (medical)


Dive into the research topics of 'The NOX1 isoform of NADPH oxidase is involved in dysfunction of liver sinusoids in nonalcoholic fatty liver disease'. Together they form a unique fingerprint.

Cite this