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, Xiaosong Jiang, Kanji Yamaguchi, Akiyuki Taruno, Masato Katsuyama, Kazumi Iwata, Masakazu Ibi, Wenhao Cui, Kuniharu Matsuno, Yoshinori Marunaka, Yoshito Itoh, Natalia J Torok, Chihiro Yabe-Nishimura

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

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
Volume115
DOIs
StatePublished - Feb 1 2018

Fingerprint

NADPH Oxidase
Liver
Liver Diseases
Protein Isoforms
Endothelial cells
Endothelial Cells
Palmitic Acid
Reactive Oxygen Species
Peroxynitrous Acid
High Fat Diet
Nutrition
Nitric Oxide
Up-Regulation
Fats
Cholesterol
Non-alcoholic Fatty Liver Disease
Microcirculation
Hepatic Stellate Cells
Messenger RNA
Wounds and Injuries

Keywords

  • 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)

Cite this

The NOX1 isoform of NADPH oxidase is involved in dysfunction of liver sinusoids in nonalcoholic fatty liver disease. / Matsumoto, Misaki; Zhang, Jia; Zhang, Xueqing; Liu, Junjie; Jiang, Xiaosong; Yamaguchi, Kanji; Taruno, Akiyuki; Katsuyama, Masato; Iwata, Kazumi; Ibi, Masakazu; Cui, Wenhao; Matsuno, Kuniharu; Marunaka, Yoshinori; Itoh, Yoshito; Torok, Natalia J; Yabe-Nishimura, Chihiro.

In: Free Radical Biology and Medicine, Vol. 115, 01.02.2018, p. 412-420.

Research output: Contribution to journalArticle

Matsumoto, M, Zhang, J, Zhang, X, Liu, J, Jiang, X, Yamaguchi, K, Taruno, A, Katsuyama, M, Iwata, K, Ibi, M, Cui, W, Matsuno, K, Marunaka, Y, Itoh, Y, Torok, NJ & Yabe-Nishimura, C 2018, 'The NOX1 isoform of NADPH oxidase is involved in dysfunction of liver sinusoids in nonalcoholic fatty liver disease', Free Radical Biology and Medicine, vol. 115, pp. 412-420. https://doi.org/10.1016/j.freeradbiomed.2017.12.019
Matsumoto, Misaki ; Zhang, Jia ; Zhang, Xueqing ; Liu, Junjie ; Jiang, Xiaosong ; Yamaguchi, Kanji ; Taruno, Akiyuki ; Katsuyama, Masato ; Iwata, Kazumi ; Ibi, Masakazu ; Cui, Wenhao ; Matsuno, Kuniharu ; Marunaka, Yoshinori ; Itoh, Yoshito ; Torok, Natalia J ; Yabe-Nishimura, Chihiro. / The NOX1 isoform of NADPH oxidase is involved in dysfunction of liver sinusoids in nonalcoholic fatty liver disease. In: Free Radical Biology and Medicine. 2018 ; Vol. 115. pp. 412-420.
@article{c016ac8b987543e7b6efb835b7ad650f,
title = "The NOX1 isoform of NADPH oxidase is involved in dysfunction of liver sinusoids in nonalcoholic fatty liver disease",
abstract = "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.",
keywords = "Liver sinusoidal endothelial cells (LSECs), Nitric oxide (NO), Nitrotyrosine, Nonalcoholic fatty liver disease (NAFLD), Reactive oxygen species (ROS)",
author = "Misaki Matsumoto and Jia Zhang and Xueqing Zhang and Junjie Liu and Xiaosong Jiang and Kanji Yamaguchi and Akiyuki Taruno and Masato Katsuyama and Kazumi Iwata and Masakazu Ibi and Wenhao Cui and Kuniharu Matsuno and Yoshinori Marunaka and Yoshito Itoh and Torok, {Natalia J} and Chihiro Yabe-Nishimura",
year = "2018",
month = "2",
day = "1",
doi = "10.1016/j.freeradbiomed.2017.12.019",
language = "English (US)",
volume = "115",
pages = "412--420",
journal = "Free Radical Biology and Medicine",
issn = "0891-5849",
publisher = "Elsevier Inc.",

}

TY - JOUR

T1 - The NOX1 isoform of NADPH oxidase is involved in dysfunction of liver sinusoids in nonalcoholic fatty liver disease

AU - Matsumoto, Misaki

AU - Zhang, Jia

AU - Zhang, Xueqing

AU - Liu, Junjie

AU - Jiang, Xiaosong

AU - Yamaguchi, Kanji

AU - Taruno, Akiyuki

AU - Katsuyama, Masato

AU - Iwata, Kazumi

AU - Ibi, Masakazu

AU - Cui, Wenhao

AU - Matsuno, Kuniharu

AU - Marunaka, Yoshinori

AU - Itoh, Yoshito

AU - Torok, Natalia J

AU - Yabe-Nishimura, Chihiro

PY - 2018/2/1

Y1 - 2018/2/1

N2 - 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.

AB - 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.

KW - Liver sinusoidal endothelial cells (LSECs)

KW - Nitric oxide (NO)

KW - Nitrotyrosine

KW - Nonalcoholic fatty liver disease (NAFLD)

KW - Reactive oxygen species (ROS)

UR - http://www.scopus.com/inward/record.url?scp=85039435136&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85039435136&partnerID=8YFLogxK

U2 - 10.1016/j.freeradbiomed.2017.12.019

DO - 10.1016/j.freeradbiomed.2017.12.019

M3 - Article

C2 - 29274380

AN - SCOPUS:85039435136

VL - 115

SP - 412

EP - 420

JO - Free Radical Biology and Medicine

JF - Free Radical Biology and Medicine

SN - 0891-5849

ER -