NADPH oxidase mediated oxidative stress in hepatic fibrogenesis

Abstract

NADPH oxidase (NOX) is a multicomponent enzyme complex that generates reactive oxygen species (ROS) in response to a wide range of stimuli. ROS is involved as key secondary messengers in numerous signaling pathways, and NADPH oxidases complex has been increasingly recognized as key elements of intracellular signaling of hepatic fibrogenesis. In the liver, NADPH oxidase is functionally expressed both in the phagocytic form and in the non-phagocytic form. The non-phagocytic NADPH oxidase complex is structurally and functionally similar to the phagocytic NADPH, resulting in reduction of molecular oxygen to generate superoxide. There are six homologous NOX proteins in the non-phagocytic forms of NADPH oxidase. An emerging concept is that both phagocytic and nonphagocytic NADPH oxidase components in hepatic stellate cells (HSCs) mediate hepatic fibrosis, suggesting its potential role as a pharmacological target for anti-fibrotic therapy. The molecular components and signaling pathways of various NADPH oxidase homologues that are critical for the fibrotic activity in HSCs need to be more clearly identified.

Figure 1

Structure of phagocytic NOX2 and non-phagocytic NOX1 complex. NOX, NADPH oxidase; NOXO, NADPH oxidase organizer; NOXA, NADPH oxidase activator; Rac, Ras-related C3 botulinum toxin substrate.

Figure 2

Profibrogenic role of NADPH oxidase-derived ROS in hepatic stellate cells. Ang II, angiotensin II; PDGF, platelet derived growth factor; AT1R; angiotensin type 1 receptor; ObR, leptin receptor; PDGFR, PDGF receptor; NOX, NADPH oxidase; ROS, reactive oxygen species; TGF, transforming growth factor; MAPK, mitogen activated protein kinase; PI3K, phosphatidylinositol 3-kinase; PTEN, phosphatase and tensin homologue; ERK, extracellular signal-regulated kinase; JNK, c-Jun N-terminal kinase; Akt, protein kinase B.