Heme Oxygenase‐1 Suppresses Wnt Signaling Pathway in Nonalcoholic Steatohepatitis‐Related Liver Fibrosis

Abstract

Background and Aim. Heme oxygenase-1 (HO-1) has been verified to play an important role in nonalcoholic steatohepatitis (NASH), but the mechanism remains unclear. In this study, we aimed to clarify whether induction of HO-1 reverses steatofibrosis via suppression of the Wnt signaling pathway and to explore the potential mechanism of HO-1 on NASH-related liver fibrosis. Methods. Mice were fed with a methionine-choline-deficient (MCD) diet for 8 weeks to induce steatohepatitis-related liver fibrosis and were treated with HO-1 inducer Hemin and inhibitor ZnPP. Mouse sera were collected for the biochemical analysis, and livers were obtained for further histological observation and gene expression analysis. HSC-T6 cells were cultured for the in vitro study and were administrated with Hemin and si-HO-1 to induce or inhibit the expression of HO-1. qPCR and Western blot were used to assess the mRNA and protein levels of genes. Results. MCD-fed mice developed marked macrovesicular steatosis, focal necrosis, and inflammatory infiltration and pericellular fibrosis in liver sections. Administration of Hemin could significantly ameliorate the severity of steatosis, inflammation, and fibrosis and also could decrease the serum ALT and AST. We demonstrated that HO-1 induction was able to downregulate the key regulator of the canonical Wnt pathway Wnt1 and the noncanonical Wnt pathway Wnt5a. The downstream factors of the Wnt pathway β-catenin and NFAT5 were inhibited by Hemin, but GSK-3β was upregulated compared to the MCD group, which were consistent with the in vitro study. Hemin markedly inhibited the TGF-β1/Smad signaling pathway in both in vivo and in vitro studies. Conclusion. Our study demonstrated that HO-1 inhibited the activation of canonical and noncanonical Wnt signaling pathways in NASH-related liver fibrosis. Thus, these results may suggest a new therapeutic strategy for NASH-related liver fibrosis.

Heme Oxygenase-1 Inhibits the Proliferation of Hepatic Stellate Cells by Activating PPARγ and Suppressing NF-κB

“…Heme oxygenase-1 (HO-1), as a rate-limiting enzyme, degrades the heme into iron, biliverdin, and carbon monoxide, which share antioxidative, anti-inflammatory, and antiapoptotic activities [ 5 ]. Increasing evidence supports that HO-1 can protect liver cells from damage caused by multiple causes, such as acute liver injury and liver transplantation [ 6 ]. Studies have shown that the HO-1 promoter region contains binding sites of NF- κ B; therefore, HO-1 activity is directly related to NF- κ B [ 7 ].…”

“…In the previous study, Du et al, have endeavored to investigate the relationship between HO-1 and nonalcoholic fatty liver disease (NAFLD) and demonstrated that the induction of HO-1 could eliminate steatohepatitis and hepatic fibrosis in the progression of NAFLD [ 6 ], thus substantiating a significant role of HO-1 against heme-mediated steatohepatitis-related liver fibrosis.…”

MCD Diet Modulates HuR and Oxidative Stress-Related HuR Targets in Rats

“…HO-1 also has a role in NASH pathogenesis. Recently, it was found that the administration of the HO-1 inducer hemin significantly ameliorates the severity of steatosis, inflammation, and fibrosis and also decreases the serum ALT and AST levels by inhibiting the activation of canonical and noncanonical Wnt signaling pathways in MCD mice [ 57 ]. Furthermore, a dramatic decrease in hepatic ROS, in association with a reduction in endoplasmic reticulum stress, was observed in mice fed with an MCD diet when treated with hemin [ 58 ].…”

Heme Oxygenase-1 Induction by Cobalt Protoporphyrin Ameliorates Cholestatic Liver Disease in a Xenobiotic-Induced Murine Model

“…Barikbin et al investigated the effects of HO-1 induction in Mdr2-knockout mice [ 34 ]; they found that the administration of CoPP effectively suppressed liver inflammation and fibrosis in the genetic animal model of chronic liver disease [ 34 ]. Recent studies have also shown that inflammatory and fibrotic changes in fatty liver disease were effectively attenuated by HO-1 induction [ 35 , 36 ]. In addition, pharmacological or genetic induction of HO-1 suppressed carbon-tetrachloride-induced liver fibrosis in rodents [ 37 , 38 ].…”