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Publication
Hepatocyte Nicotinamide Adenine Dinucleotide Phosphate Reduced Oxidase 4
Regulates Stress Signaling, Fibrosis, and Insulin Sensitivity During Development
of Steatohepatitis in Mice.
Authors Bettaieb A, Jiang JX, Sasaki Y, Chao TI, Kiss Z, Chen X, Tian J, Katsuyama M,
Yabe-Nishimura C, Xi Y, Szyndralewiez C, Schroder K, Shah A, Brandes RP, Haj FG,
Torok NJ
Submitted By Submitted Externally on 11/3/2015
Status Published
Journal Gastroenterology
Year 2015
Date Published 8/1/2015
Volume : Pages 149 : 468 - 80.e10
PubMed Reference 25888330
Abstract 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.,
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-2a kinase-mediated stress signaling pathways. We performed
hyperinsulinemic-euglycemic clamp studies and immunoprecipitation analyses to
determine the oxidation and phosphatase activity of PP1C., 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., 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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