Abstract
Reactive oxygen species (ROS) produced by nicotinamide adenine dinucleotide phosphate oxidase (NOX) play a key role in liver injury and fibrosis. Previous studies demonstrated that GKT137831, a dual NOX1/4 inhibitor, attenuated liver fibrosis in mice as well as pro-fibrotic genes in hepatic stellate cells (HSCs) as well as hepatocyte apoptosis. The effect of NOX1 and NOX4 deficiency in liver fibrosis is unclear, and has never been directly compared. HSCs are the primary myofibroblasts in the pathogenesis of liver fibrosis. Therefore, we aimed to determine the role of NOX1 and NOX4 in liver fibrosis, and investigated whether NOX1 and NOX4 signaling mediates liver fibrosis by regulating HSC activation. Mice were treated with carbon tetrachloride (CCl4) to induce liver fibrosis. Deficiency of either NOX1 or NOX4 attenuates liver injury, inflammation, and fibrosis after CCl4 compared to wild-type mice. NOX1 or NOX4 deficiency reduced lipid peroxidation and ROS production in mice with liver fibrosis. NOX1 and NOX4 deficiency are approximately equally effective in preventing liver injury in the mice. The NOX1/4 dual inhibitor GKT137831 suppressed ROS production as well as inflammatory and proliferative genes induced by lipopolysaccharide (LPS), platelet-derived growth factor (PDGF), or sonic hedgehog (Shh) in primary mouse HSCs. Furthermore, the mRNAs of proliferative and pro-fibrotic genes were downregulated in NOX1 and NOX4 knock-out activated HSCs (cultured on plastic for 5 days). Finally, NOX1 and NOX4 protein levels were increased in human livers with cirrhosis compared with normal controls. Thus, NOX1 and NOX4 signaling mediates the pathogenesis of liver fibrosis, including the direct activation of HSC.
Highlights
Liver fibrosis occurs as a result of chronic liver disease and is associated with severe morbidity and mortality [1]
We report for the first time a direct comparison of the long-term effects of NOX1 and NOX4 deficiency in the development and progression of liver fibrosis, by comparing liver fibrosis in CCl4-induced NOX1KO and NOX4KO mice and their respective wild-type (WT) littermates
Hepatic fibrosis was significantly decreased in NOX1KO and NOX4KO mice compared with WT mice after CCl4 injections (Fig 1A and 1C)
Summary
Liver fibrosis occurs as a result of chronic liver disease and is associated with severe morbidity and mortality [1]. Chronic oxidative stress is an important etiological factor in initiating the fibrogenic process in the liver [2]. Hepatic stellate cells (HSCs) are endogenous, liver-specific mesenchymal cells that play pivotal roles in liver inflammation and fibrogenesis [1]. In the PLOS ONE | DOI:10.1371/journal.pone.0129743 July 29, 2015
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