Abstract
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.
Highlights
Nonalcoholic fatty liver disease (NAFLD) has been recognized as the most important cause of chronic liver disease in developed countries and has been of considerable interest in recent years [1]
These results demonstrated that Heme oxygenase-1 (HO-1) induction alleviated liver injury and hepatic fibrosis in MCD diet-induced steatohepatitis
To clarify the pathophysiological mechanisms of nonalcoholic steatohepatitis (NASH), an ideal NASH animal model should replicate the pathophysiology of human patients, including insulin resistance, steatohepatitis, and liver fibrosis
Summary
Nonalcoholic fatty liver disease (NAFLD) has been recognized as the most important cause of chronic liver disease in developed countries and has been of considerable interest in recent years [1]. Suppression of oxidative stress could provide a therapeutic alternative in the treatment of NASH-related liver fibrosis. 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. 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. Our study demonstrated that HO-1 inhibited the activation of canonical and noncanonical Wnt signaling pathways in NASH-related liver fibrosis. These results may suggest a new therapeutic strategy for NASH-related liver fibrosis
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