Inhibition of heme-thiolate monooxygenase CYP1B1 prevents hepatic stellate cell activation and liver fibrosis by accumulating trehalose

Hung Chun Tung, Jong Won Kim, Junjie Zhu, Sihan Li, Jiong Yan, Qing Liu, Imhoi Koo, Sergei A. Koshkin, Fuhua Hao, Guo Zhong, Meishu Xu, Zehua Wang, Jingyuan Wang, Yixian Huang, Yue Xi, Xinran Cai, Pengfei Xu, Songrong Ren, Takanobu Higashiyama, Frank J. GonzalezSong Li, Nina Isoherranen, Da Yang, Xiaochao Ma, Andrew D. Patterson, Wen Xie

Research output: Contribution to journalArticlepeer-review

Abstract

Activation of extracellular matrix–producing hepatic stellate cells (HSCs) is a key event in liver fibrogenesis. We showed that the expression of the heme-thiolate monooxygenase cytochrome P450 1B1 (CYP1B1) was elevated in human and mouse fibrotic livers and activated HSCs. Systemic or HSC-specific ablation and pharmacological inhibition of CYP1B1 attenuated HSC activation and protected male but not female mice from thioacetamide (TAA)–, carbon tetrachloride (CCl4)–, or bile duct ligation (BDL)–induced liver fibrosis. Metabolomic analysis revealed an increase in the disaccharide trehalose in CYP1B1-deficient HSCs resulting from intestinal suppression of the trehalose-metabolizing enzyme trehalase, whose gene we found to be a target of RARα. Trehalose or its hydrolysis-resistant derivative lactotrehalose exhibited potent antifibrotic activity in vitro and in vivo by functioning as an HSC-specific autophagy inhibitor, which may account for the antifibrotic effect of CYP1B1 inhibition. Our study thus reveals an endobiotic function of CYP1B1 in liver fibrosis in males, mediated by liver-intestine cross-talk and trehalose. At the translational level, pharmacological inhibition of CYP1B1 or the use of trehalose/lactotrehalose may represent therapeutic strategies for liver fibrosis.

Original languageEnglish (US)
Article numbereadk8446
JournalScience Translational Medicine
Volume16
Issue number766
DOIs
StatePublished - Sep 25 2024

All Science Journal Classification (ASJC) codes

  • General Medicine

Fingerprint

Dive into the research topics of 'Inhibition of heme-thiolate monooxygenase CYP1B1 prevents hepatic stellate cell activation and liver fibrosis by accumulating trehalose'. Together they form a unique fingerprint.

Cite this