Cellular and Metabolic Basis of the Role of CYP1B1 in Liver Fibrosis

University Of Pittsburgh At Pittsburgh, Pittsburgh PA

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Abstract

Title: Cellular and Metabolic Basis of the Role of CYP1B1 in Liver Fibrosis Abstract Liver fibrosis is often resulted from chronic liver injury. Hepatic stellate cells (HSCs) are the primary hepatic myofibroblasts responsible for the production of extracellular matrix proteins. As such, activation of HSCs is central to the pathogenesis of liver fibrosis. There are no FDA approved anti-liver fibrosis drugs. Understanding the molecular basis of HSC activation will help to develop strategies to treat liver fibrosis. Among the proposed mechanisms of HSC activation, autophagy activation has been shown to promote HSC activation. The cytochrome P450 1B1 (CYP1B1) is a NADPH-dependent heme-thiolate monooxygenase initially recognized as a xenobiotic enzyme that metabolizes xenobiotics. Subsequent studies suggest that CYP1B1 also has endobiotic functions by metabolizing endobiotics. The role of CYP1B1 in liver fibrosis has not been reported. The liver is an organ of multiple cell types. It is unclear whether CYP1B1 has a cell-type specific role in liver fibrosis. Specifically, whether and how CYP1B1 plays a role in HSC activation and liver fibrosis warrant studies. Our preliminary results showed that: 1) The expression of CYP1B1 is induced in fibrotic human and mouse livers; 2) CYP1B1 is highly expressed in primary mouse and human HSCs, and the expression of CYP1B1 increases with the onset of HSC activation independent of AhR; 3) Ablation or pharmacological inhibition of CYP1B1 inhibits HSC activation; 4) Whole-body knockout of Cyp1b1 inhibits liver fibrosis in vivo; 5) Metabolomic analysis reveals that HSCs isolated from Cyp1b1 KO mice have an accumulation of trehalose, a non-reducing disaccharides; 6) Trehalose inhibits HSC activation and liver fibrosis by functioning as an HSC specific autophagy inhibitor; 7) The accumulation of trehalose in Cyp1b1 KO mice is accompanied by the intestinal suppression of trehalase (Treh), the trehalose-metabolizing enzyme; and 8) The Cyp1b1 and Treh genes are putative transcriptional targets of Wilms’ tumor 1 (WT1) and RARa, respectively. Based on our preliminary data, we hypothesize that Cyp1b1 has a cell-type specific role in HSC activation and liver fibrosis. Specifically, we hypothesize that HSC and/or HEP ablation or pharmacological inhibition of Cyp1b1 inhibits HSC activation and liver fibrosis. Mechanistically, inhibition of Cyp1b1 attenuates HSC activation by suppressing the intestinal trehalase, leading to the accumulation of trehalose, a non-reducing disaccharide that can inhibit HSC activation and liver fibrosis. We propose four specific aims to test our hypothesis: 1) To determine the cell-type specific role of Cyp1b1 in liver fibrosis in vivo; 2) To determine whether pharmacological inhibition of Cyp1b1 inhibits liver fibrosis in vivo; 3) To determine the role of trehalose and trehalase (Treh) in mediating the anti-fibrotic effect of Cyp1b1 inhibition; and 4) To determine the transcriptional mechanism of fibrosis-responsive induction of Cyp1b1 and Cyp1b1 inhibition-responsive suppression of trehalase. This study represents the first attempt to evaluate the cell-type specific role of CYP1B1 in liver fibrosis. Our study will uncover a previously unrecognized endobiotic function of CYP1B1 in liver fibrosis mediated by the liver-intestine organ crosstalk and the trehalose metabolite. Trehalose is a novel anti-fibrotic agent that inhibits HSC activation by functioning as an HSC-specific autophagy inhibitor. Pharmacological inhibition of Cyp1b1 and/or the use of trehalose represent novel strategies for the clinical management of liver fibrosis.