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

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.

Phytochemical Profiling and Anti-Fibrotic Activities of the Gemmotherapy Bud Extract of Corylus avellana in a Model of Liver Fibrosis on Diabetic Mice

“…The up-regulation of HO-1 could protect the liver against inflammation via its products, CO, and biliverdin [ 29 ]. Recent studies proved that HO-1 induction could inhibit hepatic stellate cell proliferation [ 30 ] and, as a result, the expression of -SMA decreased, as was shown in our study too.…”

Coral calcium carried hydrogen ameliorates the severity of non-alcoholic steatohepatitis induced by a choline deficient high carbohydrate fat-free diet in elderly rats

“…Other reasons may include induction of anti-inflammatory molecules. The trend toward enhanced mRNA expression of HO-1 was observed by G2-SUISO administration (data not shown) and several studies demonstrated that HO-1 inhibit NF-κB 29 – 31 .…”

Berberine through PPAR- γ/HO-1 Pathway Regulates Macrophage Polarization

“…Therefore, the activation of HO-1 was considered to be essential for the anti-in ammatory effect of PPAR-γ, and the interaction between HO-1 and PPAR-γ was also proved [23]. Hui Yang's study also indicated that the activation and expression of HO-1 could increase the expression of PPAR-γ; that is, the expression level of PPAR-γ would change with the change of the expression level of HO-1 [24]. This is consistent with our results that PPAR-γ and HO-1 can regulate and in uence each other.…”