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

Hui Yang,Zhongfu Zhao,Li Zhang,Jie Chen,Xiaoqian Zhang,Longfeng Zhao

doi:10.1155/2022/8920861

Abstract

Background Hepatic stellate cells (HSCs) are reported to play significant roles in the development of liver fibrosis. Heme oxygenase-1 (HO-1) is a key rate-limiting enzyme, which could decrease collagen synthesis and liver damage. Nevertheless, it was yet elusive towards the function and mechanism of HO-1. Methods An HO-1 inducer Hemin or an HO-1 inhibitor ZnPP-IX was used to treat the activated HSC-T6, respectively. MTT assay was adopted to detect cell proliferation. Immunocytochemical staining was employed to test the levels of alpha-smooth muscle actin (α-SMA), peroxisome proliferator-activated receptor-γ (PPARγ), and nuclear factor-kappa B (NF-kappa B) levels in HSC-T6. HO-1, PPARγ, and NF-κB expression levels were measured by qRT-PCR and Western blotting. ELISA was then used to detect the levels of transforming growth factor- (TGF-) beta 1 (TGF-β1), interleukin-6 (IL-6), serum hyaluronic acid (HA), and serum type III procollagen aminopeptide (PIIIP). Results HSC-T6 proliferation was inhibited in Hemin-treated HSCs. The levels of α-SMA, HA, and PIIIP and the production of ECM were lower in Hemin-treated HSCs, whereas those could be rescued by ZnPP-IX. NF-κB activation was decreased, but PPARγ expression was increased after HO-1 upregulation. Furthermore, the levels of TGF-β1 and IL-6, which were downstream of activated NF-κB in HSC-T6, were reduced. The PPAR-specific inhibitor GW9662 could block those mentioned effects. Conclusions Our data demonstrated that HO-1 induction could inhibit HSC proliferation and activation by regulating PPARγ expression and NF-κB activation directly or indirectly, which makes it a promising therapeutic target for liver fibrosis.

Highlights

Hepatic stellate cells (HSCs) are reported to play significant roles in liver fibrosis progression
These results indicated that high concentrations of Hemin or ZnPP-IX and long incubation periods were toxic to cultured HSC-T6
Our recent studies in the CCl4-induced rat liver fibrosis model have suggested that the induction of Heme oxygenase-1 (HO-1) expression results in an apparent reduction in the α-smooth muscle actin (α-SMA) level, collagen synthesis, and liver damage, thereby preventing the progression of liver fibrosis

Summary

Introduction

Hepatic stellate cells (HSCs) are reported to play significant roles in liver fibrosis progression. Preventing the proliferation and activation of HSCs is an effective strategy to reverse liver fibrosis. NF-κB is associated with the phenotype of the HSCs. Activated NF-κB promotes the proliferation and ECM production of HSC, which is significant in the process of liver fibrosis [1]. PPARγ upregulation leads to a significant decrease in HSC activation and reverses the progression of liver fibrosis. Hepatic stellate cells (HSCs) are reported to play significant roles in the development of liver fibrosis. Our data demonstrated that HO-1 induction could inhibit HSC proliferation and activation by regulating PPARγ expression and NF-κB activation directly or indirectly, which makes it a promising therapeutic target for liver fibrosis

Methods

Results

Conclusion