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

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2024 · $400,107

## 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 fibr...

## Key facts

- **NIH application ID:** 10828410
- **Project number:** 5R01DK135538-02
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Wen Xie
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $400,107
- **Award type:** 5
- **Project period:** 2023-04-15 → 2027-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10828410

## Citation

> US National Institutes of Health, RePORTER application 10828410, Cellular and Metabolic Basis of the Role of CYP1B1 in Liver Fibrosis (5R01DK135538-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10828410. Licensed CC0.

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