Hepatocyte nicotinamide adenine dinucleotide phosphate reduced oxidase 4 regulates stress signaling, fibrosis, and insulin sensitivity during development of steatohepatitis in mice
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Background & aims Reactive oxidative species (ROS) are believed to be involved in the progression of nonalcoholic steatohepatitis (NASH). However, little is known about the sources of ROS in hepatocytes or their role in disease progression. We studied the effects of nicotinamide adenine dinucleotide phosphate reduced oxidase 4 (NOX4) in liver tissues from patients with NASH and mice with steatohepatitis. Methods Liver biopsy samples were obtained from 5 patients with NASH, as well as 4 patients with simple steatosis and 5 patients without steatosis (controls) from the University of California, Davis Cancer Center Biorepository. Mice with hepatocyte-specific deletion of NOX4 (NOX4(hepKO)) and NOX4(floxp+/+) C57BL/6 mice (controls) were given fast-food diets (supplemented with high-fructose corn syrup) or choline-deficient l-amino acid defined diets to induce steatohepatitis, or control diets, for 20 weeks. A separate group of mice were given the NOX4 inhibitor (GKT137831). Liver tissues were collected and immunoblot analyses were performed determine levels of NOX4, markers of inflammation and fibrosis, double-stranded RNA-activated protein kinase, and phospho-eIF-2α kinase-mediated stress signaling pathways. We performed hyperinsulinemic-euglycemic clamp studies and immunoprecipitation analyses to determine the oxidation and phosphatase activity of PP1C. Results Levels of NOX4 were increased in patients with NASH compared with controls. Hepatocyte-specific deletion of NOX4 reduced oxidative stress, lipid peroxidation, and liver fibrosis in mice with diet-induced steatohepatitis. A small molecule inhibitor of NOX4 reduced liver inflammation and fibrosis and increased insulin sensitivity in mice with diet-induced steatohepatitis. In primary hepatocytes, NOX4 reduced the activity of the phosphatase PP1C, prolonging activation of double-stranded RNA-activated protein kinase and phosphorylation of extracellular signal-regulated kinase-mediated stress signaling. Mice with hepatocyte-specific deletion of NOX4 and mice given GKT137831 had increased insulin sensitivity. Conclusions NOX4 regulates oxidative stress in the liver and its levels are increased in patients with NASH and mice with diet-induced steatohepatitis. Inhibitors of NOX4 reduce liver inflammation and fibrosis and increase insulin sensitivity, and might be developed for treatment of NASH.
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No direct antioxidative side effects of GKT137831 have been reported so far, highlighting it as the most promising inhibitor for Nox enzymes in vitro and in vivo.
“In contrast, so far no direct antioxidative side effects of GKT 137831 were reported [392] highlighting this substance as the most promising inhibitor for Nox enzymes not only in vitro but also in vivo [94,409,411,412,413,414].”
From Functions of ROS in Macrophages and Antimicrobial Immunity (2021) · cites this paper as [414]
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- Authors
- Bettaieb, A., Jiang, J. X., Sasaki, Y., Chao, T.-I., Kiss, Z., Chen, X., Tian, J., Katsuyama, M., Yabe-Nishimura, C., Xi, Y., Szyndralewiez, C., Schröder, K., Shah, A., Brandes, R. P., Haj, F. G., & Török, N. J.
- Affiliations
- University of California, Davis (US)
- Sacramento VA Medical Center (US)
- Kyoto Prefectural University of Medicine (JP)
- Goethe University Frankfurt (DE)
- King's College London (GB)
- Venue
- Gastroenterology
- Publisher
- Elsevier BV
- Published
- 2015-08
- Volume
- 149
- Issue
- 2
- Pages
- 468-480.e10
- ISSN
- 0016-5085 (ISSN-L)
- PMC
- PMC4516583
- OpenAlex
- W1867325796
- Cited by
- 167
- References
- 55
- Citations by year
- 2026: 11 · 2025: 13 · 2024: 6 · 2023: 14 · 2022: 17 · 2021: 21 · 2020: 28 · 2019: 10 · 2018: 14 · 2017: 15 · 2016: 15 · 2015: 3
- FWCI
- 12.29
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Gastroenterology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- U.S. Department of Veterans Affairs (I01 BX002418)
- Yale University
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK090492, U24DK092993, DK095359, R56DK083283, U24DK059635, R00DK100736, DK-083283, R01DK095359, R01DK083283, DK059635, K01DK090121)
- Topics
- Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
- Keywords
- nonalcoholic steatohepatitis, NOX4, reactive oxygen species, oxidative stress, liver fibrosis, insulin sensitivity, DAPK, eIF2α phosphorylation, ERK signaling, hepatocyte-specific deletion, GKT137831, choline-deficient diet
- MeSH terms
- NADPH Oxidase 4, Animals, Biopsy, Diet, Disease Models, Animal, Fatty Liver, Humans, Insulin Resistance, Liver, Liver Cirrhosis, Mice, Inbred C57BL, NADP, Obesity, Pyrazoles, Pyridines, Pyridones, Stress, Physiological, Lipid Peroxidation, Biomarkers, Mice, Knockout, Oxidative Stress, NADPH Oxidases, Hepatocytes, Pyrazolones, Mice, Protein Phosphatase 1
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