Role of NADPH Oxidases in Liver Fibrosis

Yong Paik

Jonghwa Kim

Tomonori Aoyama

Samuele De Minicis

Ramon Bataller

David Brenner

^{Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.}

^{Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Seoul, Korea.}

^{Department of Gastroenterology, Juntendo University School of Medicine, Tokyo, Japan.}

^{Department of Gastroenterology, Università Politecnica delle Marche, Ancona, Italy.}

^{Department of Digestive Disease and Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.}

^{Department of Medicine, University of California San Diego, La Jolla, California.}

^{Corresponding author.}

Address correspondence to:, Prof. David A. Brenner, Department of Medicine, University of California San Diego, 1318A Biomedical Sciences Building, 9500 Gilman Drive, La Jolla, CA 92093-0602, E-mail:Email: ude.dscu@rennerbd

Received 2013 Sep 2; Accepted 2013 Sep 16.

Abstract

Significance: Hepatic fibrosis is the common pathophysiologic process resulting from chronic liver injury, characterized by the accumulation of an excessive extracellular matrix. Multiple lines of evidence indicate that oxidative stress plays a pivotal role in the pathogenesis of liver fibrosis. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) is a multicomponent enzyme complex that generates reactive oxygen species (ROS) in response to a wide range of stimuli. In addition to phagocytic NOX2, there are six nonphagocytic NOX proteins. Recent Advances: In the liver, NOX is functionally expressed both in the phagocytic form and in the nonphagocytic form. NOX-derived ROS contributes to various kinds of liver disease caused by alcohol, hepatitis C virus, and toxic bile acids. Recent evidence indicates that both phagocytic NOX2 and nonphagocytic NOX isoforms, including NOX1 and NOX4, mediate distinct profibrogenic actions in hepatic stellate cells, the main fibrogenic cell type in the liver. The critical role of NOX in hepatic fibrogenesis provides a rationale to assess pharmacological NOX inhibitors that treat hepatic fibrosis in patients with chronic liver disease. Critical Issues: Although there is compelling evidence indicating a crucial role for NOX-mediated ROS generation in hepatic fibrogenesis, little is known about the expression, subcellular localization, regulation, and redox signaling of NOX isoforms in specific cell types in the liver. Moreover, the exact mechanism of NOX-mediated fibrogenic signaling is still largely unknown. Future Directions: A better understanding through further research about NOX-mediated fibrogenic signaling may enable the development of novel anti-fibrotic therapy using NOX inhibition strategy. Antioxid. Redox Signal. 20, 2854–2872.

Abstract

Abbreviations Used

ACE	angiotensin converting enzyme
ACEi	angiotensin-converting enzyme inhibitor
Akt	protein kinase B
ALS	amyotrophic lateral sclerosis
Ang II	angiotensin II
AP	activator protein
ARB	angiotensin receptor blocker
AT1R	angiotensin type I receptor
ATF	activating transcription factor
BDL	bile duct ligation
CGD	chronic granulomatous disease
CYP	cytochrome p450
DPI	diphenylene iodonium
ECM	extracellular matrix
ECs	endothelial cells
EGF	epidermal growth factor
EGFR	epidermal growth factor receptor
ER	endoplasmic reticulum
ERK	extracellular signal-regulated kinase
H₂O₂	hydrogen peroxide
HBV	hepatitis B virus
HCC	hepatocellular carcinoma
HCV	hepatitis C virus
HSCs	hepatic stellate cells
IFN	interferon
IRAK	IL-1R-associated kinase
JNK	c-Jun-N-terminal kinase
KCs	Kupffer cells
NADPH	nicotinamide adenine dinucleotide phosphate
NASH	nonalcoholic steatohepatitis
NOX	NADPH oxidase
PKC	protein kinase C
PLs	phospholipases
PTEN	phosphatase and tensin homologue
RAS	renin-angiotensin system
ROS	reactive oxygen species
SOD	superoxide dismutase
TLR	toll-like receptor
VSMCs	vascular smooth muscle cells
WT	wild-type

Abbreviations Used

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