Inhibition of Cytochrome P450 1B1 Prevents Hepatic Stellate Cell Activation and Liver Fibrosis

Abstract

Background : Liver fibrosis often results from chronic liver injury and it is characterized by the accumulation of extracellular matrix. Activation of the hepatic stellate cell (HSC) is a key fibrogenic event. Cytochrome P450 1b1 (Cyp1b1) is a heme-thiolate monooxygenase involved in the metabolism of endogenous compounds and xenobiotics. The goal of this study is to determine whether and how Cyp1b1 plays a role in hepatic stellate cell (HSC) activation and liver fibrosis. Methods : The effects of Cyp1b1 on HSC activation and fibrogenesis were assessed by real-time PCR, immunofluorescence, and RNA-seq analysis. Wild-type (WT) and Cyp1b1 knockout (Cyp1b1-/-) mice were subjected to thioacetamide (TAA), carbon tetrachloride (CCl4), or bile duct ligation (BDL) models of liver fibrosis, and the fibrosis phenotypes were analyzed at the histology and gene expression levels. Hepatic retinoid levels were measured by liquid chromatography-mass spectrometry (LC-MS/MS). Results : Cyp1b1 is highly expressed in HSCs. The expression of Cyp1b1 was elevated in fibrotic mouse and human livers, as well as in activated mouse and human HSCs. In contrast, down-regulation or pharmacological inhibition of Cyp1b1 by 2,4,3′,5′-tetramethoxystilbene (TMS) attenuated HSC activation in vitro and in vivo. Cyp1b1-/- mice or WT mice treated with TMS were protected from liver fibrosis. Mechanistically, the fibrogenic induction of Cyp1b1 is likely mediated by the transcriptional factor wilms' tumor 1 (WT1). The pro-fibrogenic activity of Cyp1b1 may have been accounted for by its metabolism of retinoids in HSCs. Conclusion : Our study has uncovered an important endobiotic function of Cyp1b1 in promoting liver fibrosis. Cyp1b1 promotes HSC activation and liver fibrogenesis by facilitating retinoids depletion. Pharmacological inhibition of Cyp1b1 might be a potential strategy for the treatment of liver fibrosis.