TY - JOUR
T1 - Inhibition of heme-thiolate monooxygenase CYP1B1 prevents hepatic stellate cell activation and liver fibrosis by accumulating trehalose
AU - Tung, Hung Chun
AU - Kim, Jong Won
AU - Zhu, Junjie
AU - Li, Sihan
AU - Yan, Jiong
AU - Liu, Qing
AU - Koo, Imhoi
AU - Koshkin, Sergei A.
AU - Hao, Fuhua
AU - Zhong, Guo
AU - Xu, Meishu
AU - Wang, Zehua
AU - Wang, Jingyuan
AU - Huang, Yixian
AU - Xi, Yue
AU - Cai, Xinran
AU - Xu, Pengfei
AU - Ren, Songrong
AU - Higashiyama, Takanobu
AU - Gonzalez, Frank J.
AU - Li, Song
AU - Isoherranen, Nina
AU - Yang, Da
AU - Ma, Xiaochao
AU - Patterson, Andrew D.
AU - Xie, Wen
N1 - Publisher Copyright:
Copyright © 2024 The authors, some rights reserved.
PY - 2024/9/25
Y1 - 2024/9/25
N2 - 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.
AB - 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.
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U2 - 10.1126/scitranslmed.adk8446
DO - 10.1126/scitranslmed.adk8446
M3 - Article
C2 - 39321267
AN - SCOPUS:85204940861
SN - 1946-6234
VL - 16
JO - Science Translational Medicine
JF - Science Translational Medicine
IS - 766
M1 - eadk8446
ER -