Liver fibrosis and hepatocyte apoptosis are attenuated by GKT137831, a novel NOX4/NOX1 inhibitor in vivo

Xiaosong Jiang, Xiangling Chen, Nobuko Serizawa, Cédric Szyndralewiez, Patrick Page, Katrin Schröder, Ralf P. Brandes, Sridevi Devaraj, Natalia J Torok

Research output: Contribution to journalArticle

137 Citations (Scopus)

Abstract

Reactive oxygen species (ROS) play a key role in chronic liver injury and fibrosis. Homologs of NADPH oxidases (NOXs) are major sources of ROS, but the exact role of the individual homologs in liver disease is unknown. Our goal was to determine the role of NOX4 in liver fibrosis induced by bile duct ligation (BDL) with the aid of the pharmacological inhibitor GKT137831, and genetic deletion of NOX4 in mice. GKT137831 was either applied for the full term of BDL (preventive arm) or started at 10 day postoperatively (therapeutic arm). Primary hepatic stellate cells (HSC) from control mice with and without BDL were analyzed and the effect of NOX4 inhibition on HSC activation was also studied. FasL or TNFα/actinomycin D-induced apoptosis was studied in wild-type and NOX4-/- hepatocytes. NOX4 was upregulated by a TGF-β/Smad3- dependent mechanism in HSC. Downregulation of NOX4 decreased ROS production and the activation of NOX4-/- HSC was attenuated. NOX4-/- hepatocytes were more resistant to FasL or TNFα/actinomycin D-induced apoptosis. Similarly, after pharmacological NOX4 inhibition, ROS production, the expression of fibrogenic markers, and hepatocyte apoptosis were reduced. NOX4 was expressed in human livers with stage 2-3 autoimmune hepatitis. Fibrosis was attenuated by the genetic deletion of NOX4. BDL mice gavaged with GKT137831 in the preventive or the therapeutic arm displayed less ROS production, significantly attenuated fibrosis, and decreased hepatocyte apoptosis. In conclusion, NOX4 plays a key role in liver fibrosis. GKT137831 is a potent inhibitor of fibrosis and hepatocyte apoptosis; therefore, it is a promising therapeutic agent for future translational studies.

Original languageEnglish (US)
Pages (from-to)289-296
Number of pages8
JournalFree Radical Biology and Medicine
Volume53
Issue number2
DOIs
StatePublished - Jul 15 2012

Fingerprint

Hepatic Stellate Cells
Liver Cirrhosis
Liver
Hepatocytes
Reactive Oxygen Species
Bile Ducts
Ducts
Ligation
Apoptosis
Fibrosis
Dactinomycin
Chemical activation
Pharmacology
Autoimmune Hepatitis
NADPH Oxidase
Liver Diseases
Therapeutics
Down-Regulation
GKT137831
Wounds and Injuries

Keywords

  • Hepatocyte apoptosis
  • Liver fibrosis
  • NADPH oxidase 4
  • Stellate cell activation

ASJC Scopus subject areas

  • Biochemistry
  • Physiology (medical)

Cite this

Liver fibrosis and hepatocyte apoptosis are attenuated by GKT137831, a novel NOX4/NOX1 inhibitor in vivo. / Jiang, Xiaosong; Chen, Xiangling; Serizawa, Nobuko; Szyndralewiez, Cédric; Page, Patrick; Schröder, Katrin; Brandes, Ralf P.; Devaraj, Sridevi; Torok, Natalia J.

In: Free Radical Biology and Medicine, Vol. 53, No. 2, 15.07.2012, p. 289-296.

Research output: Contribution to journalArticle

Jiang, Xiaosong ; Chen, Xiangling ; Serizawa, Nobuko ; Szyndralewiez, Cédric ; Page, Patrick ; Schröder, Katrin ; Brandes, Ralf P. ; Devaraj, Sridevi ; Torok, Natalia J. / Liver fibrosis and hepatocyte apoptosis are attenuated by GKT137831, a novel NOX4/NOX1 inhibitor in vivo. In: Free Radical Biology and Medicine. 2012 ; Vol. 53, No. 2. pp. 289-296.
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