Abstract
BackgroundHeme oxygenase-1 (HO-1), an antioxidant defense enzyme, has been shown to protect against oxidant-induced liver injury. However, its role on liver fibrosis remains unclear. This study aims to elucidate the effect and the mechanism of HO-1 in nutritional fibrosing steatohepatitis in mice.MethodsMale C57BL/6J mice were fed with a methionine-choline deficient (MCD) diet for eight weeks to induce hepatic fibrosis. HO-1 chemical inducer (hemin), HO-1 chemical inhibitor zinc protoporphyrin IX (ZnPP-IX) and/or adenovirus carrying HO-1 gene (Ad-HO-1) were administered to mice, respectively. Liver injury was assessed by serum ALT, AST levels and histological examination; hepatic lipid peroxides levels were determined; the expression levels of several fibrogenic related genes were assayed by real-time quantitative PCR and Western blot.ResultsMCD feeding mice showed progressive hepatic injury including hepatic steatosis, inflammatory infiltration and fibrosis. Induction of HO-1 by hemin or Ad-HO-1 significantly attenuated the severity of liver injury. This effect was associated with the up-regulation of HO-1, reduction of hepatic lipid peroxides levels, down-regulation of inflammatory factors tumor necrosis factor-alpha, interleukin-6 and suppressor of cytokine signaling-1 as well as the pro-fibrotic genes alpha-smooth muscle actin, transforming growth factor-β1, matrix metallopeptidase-2 and matrix metallopeptidase-9. A contrary effect was observed in mice treated with ZnPP-IX.ConclusionsThe present study provided the evidence for the protective role of HO-1 in ameliorating MCD diet-induced fibrosing steatohepatitis. Modulation of HO-1 expression might serve as a therapeutic approach for fibrotic steatohepatitis.
Highlights
Non-alcoholic steatohepatitis (NASH) represents a major medical problem worldwide and has been recognized as a leading cause of liver fibrosis [1]
Effect of Heme oxygenase-1 (HO-1) on methionine-choline deficient (MCD) diet-induced fibrosing steatohepatitis Mice fed with MCD diet for 8 weeks exhibited disordered lobule structure, macrosteatosis in Zone 3, spot or focal hepatocyte necrosis, inflammatory infiltration (Figure 1A) and portal and perisinusoidal fibrosis (Figure 1B)
Treatment with Heme oxygenase (HO)-1 inducer hemin or AdHO-1 markedly reduced the severity of hepatic steatosis, inflammatory infiltration (Figure 1A) and fibrosis (Figure 1B), which was associated with a prominent decrease in serum ALT (Figure 2A), AST (Figure 2B) levels and hepatic hydroxyproline content (Figure 3A)
Summary
Non-alcoholic steatohepatitis (NASH) represents a major medical problem worldwide and has been recognized as a leading cause of liver fibrosis [1]. The progression of fibrosis is the critical pathophysiological feature of NASH, the mechanism of fibrogenesis in the presence of steatohepatitis has not been well elucidated and specific therapies are lacking. Reactive oxygen species (ROS) and oxidative stress are the major causes of liver damage and involved in the development of hepatic fibrosis by inducing hepatic stellate cells (HSC) proliferation and collagen synthesis [4]. Oxidative stress promotes pro-inflammatory cytokines secretion, such as in pathophysiological damage to the liver. Suppression oxidative stress, inhibition of HSC activation and its related subsequent events, such as increased production of ECM components and fibrogenic cytokines, could be a therapeutic approach for liver fibrosis. This study aims to elucidate the effect and the mechanism of HO-1 in nutritional fibrosing steatohepatitis in mice
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