Role of NADPH Oxidases in Liver Fibrosis

Paik, Yong Han; Kim, Jong-Hwa; Aoyama, Tomonori; Minicis, S. De; Bataller, Ramón; Brenner, David A.

doi:10.1089/ars.2013.5619

Cited by 188 publications

(171 citation statements)

References 204 publications

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“…The most common and relevant mechanisms that are recognized in hepatic fibrogenesis are the production of ROS (30) and recruitment of inflammatory cells (31), both of which were observed in the livers of TCS-treated mice. ROS generation in alcohol abuse, HCV infection, and chronic cholestasis is associated with various types of liver injuries accompanied by hepatic fibrosis (14).…”

Section: Discussionmentioning

confidence: 99%

The commonly used antimicrobial additive triclosan is a liver tumor promoter

Yueh

Taniguchi

Chen

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

198

137

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Significance Triclosan [5-chloro-2-(2,4-dichlorophenoxy)phenol; TCS] is a broad-spectrum antimicrobial agent that has become one of the most common additives used in consumer products. As a result, TCS has significantly affected the environment and has been frequently detected in human body fluids. Through a long-term feeding study, we found that TCS enhances hepatocyte proliferation, fibrogenesis, and oxidative stress, which, we believe, can be the driving force for developing advanced liver disease in mice. Indeed, TCS strongly enhances hepatocarcinogenesis after diethylnitrosamine initiation, accelerating hepatocellular carcinoma (HCC) development. Although animal studies require higher chemical concentrations than predicted for human exposure, this study demonstrates that TCS acts as a HCC tumor promoter and that the mechanism of TCS-induced mouse liver pathology may be relevant to humans.

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Section: Discussionmentioning

confidence: 99%

The commonly used antimicrobial additive triclosan is a liver tumor promoter

Yueh

Taniguchi

Chen

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

198

137

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“…19 Liver has been shown to be a rich source of various isoforms of the family of reactive oxygen speciesegenerating NADPH oxidases (NOX), being present in phagocytic Kupffer cells, stellate cells, and sinusoidal endothelial cells. 3,17,20 Out of the various NOX isoforms, NOX2 is primarily present in Kupffer cells and stellate cells, whereas NOX1 and NOX4 have been found in other liver cell types. 17 NOX2 is composed of several subunits, including glycoprotein (gp) gp91, p22 (membrane subunits), p67, p47, and Ras-related C3 botulinum toxin substrate 1 (cytosolic subunits).…”

mentioning

confidence: 99%

“…3,17,20 Out of the various NOX isoforms, NOX2 is primarily present in Kupffer cells and stellate cells, whereas NOX1 and NOX4 have been found in other liver cell types. 17 NOX2 is composed of several subunits, including glycoprotein (gp) gp91, p22 (membrane subunits), p67, p47, and Ras-related C3 botulinum toxin substrate 1 (cytosolic subunits). 19 On receipt of proper signals, the cytosolic subunits align with their membrane counterparts to form an active NADPH oxidase complex that produces superoxide radicals to be released into the extracellular space.…”

mentioning

confidence: 99%

NADPH Oxidase–Derived Peroxynitrite Drives Inflammation in Mice and Human Nonalcoholic Steatohepatitis via TLR4-Lipid Raft Recruitment

Das

Alhasson

Dattaroy

et al. 2015

The American Journal of Pathology

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The molecular events that link NADPH oxidase activation and the induction of Toll-like receptor (TLR)-4 recruitment into hepatic lipid rafts in nonalcoholic steatohepatitis (NASH) are unclear. We hypothesized that in liver, NADPH oxidase activation is key in TLR4 recruitment into lipid rafts, which in turn upregulates NF-kB translocation to the nucleus and subsequent DNA binding, leading to NASH progression. Results from confocal microscopy showed that liver from murine and human NASH had NADPH oxidase activation, which led to the formation of highly reactive peroxynitrite, as shown by 3-nitrotyrosine formation in diseased liver. Expression and recruitment of TLR4 into the lipid rafts were significantly greater in rodent and human NASH. The described phenomenon was NADPH oxidase, p47phox, and peroxynitrite dependent, as liver from p47phox-deficient mice and from mice treated with a peroxynitrite decomposition catalyst [iron(III) tetrakis(p-sulfonatophenyl)porphyrin] or a peroxynitrite scavenger (phenylboronic acid) had markedly less Tlr4 recruitment into lipid rafts. Mechanistically, peroxynitrite-induced TLR4 recruitment was linked to increased IL-1b, sinusoidal injury, and Kupffer cell activation while blocking peroxynitrite-attenuated NASH symptoms. The results strongly suggest that NADPH oxidaseemediated peroxynitrite drove TLR4 recruitment into hepatic lipid rafts and inflammation, whereas the in vivo use of the peroxynitrite scavenger phenylboronic acid, a novel synthetic molecule having high reactivity with peroxynitrite, attenuates inflammatory pathogenesis in NASH. (Am J Pathol 2015 http://dx

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“…The contribution of oxidative stress to stellate cells transformation is not solely in response to extrinsic ROS, but also from intracellular prooxidant enzymes. More specifi cally, non-phagocytic NOX production may also be involved in the transformation of stellate cells [ 80 ]. Another example is xanthine dehydrogenase, which is proteolytically cleaved to the O 2…”

Section: Increased Activity Of Prooxidant Enzymes From Noninfl Ammatomentioning

confidence: 99%