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

IF 15.8 1区 医学 Q1 CELL BIOLOGY Science Translational Medicine Pub Date : 2024-09-25 DOI:10.1126/scitranslmed.adk8446
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. Gonzalez, Song Li, Nina Isoherranen, Da Yang, Xiaochao Ma, Andrew D. Patterson, Wen Xie
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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.
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抑制血红硫酸酯单加氧酶 CYP1B1 可防止肝星状细胞活化和肝纤维化,因为它积累了三卤糖
产生细胞外基质的肝星状细胞(HSCs)的活化是肝纤维化的一个关键事件。我们发现,在人和小鼠纤维化肝脏和活化的造血干细胞中,血红硫酸酯单加氧酶细胞色素P450 1B1 (CYP1B1)的表达升高。全身或造血干细胞特异性消融和药物抑制 CYP1B1 可减轻造血干细胞的活化,并保护雄性小鼠而非雌性小鼠免受硫代乙酰胺(TAA)、四氯化碳(CCl4)或胆管结扎(BDL)诱导的肝纤维化的影响。代谢组学分析表明,CYP1B1缺陷的造血干细胞中二糖三卤糖的含量增加,这是由于肠道抑制了三卤糖代谢酶三卤糖酶,而我们发现三卤糖酶的基因是RARα的靶标。通过作为造血干细胞特异性自噬抑制剂,曲哈洛糖或其抗水解衍生物乳曲哈洛糖在体外和体内均表现出强大的抗纤维化活性,这可能是抑制 CYP1B1 的抗纤维化作用的原因。因此,我们的研究揭示了 CYP1B1 在男性肝纤维化中的内生功能,它是由肝肠交叉对话和三卤糖介导的。在转化水平上,药物抑制 CYP1B1 或使用曲哈露糖/乳曲哈露糖可能是治疗肝纤维化的策略。
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来源期刊
Science Translational Medicine
Science Translational Medicine CELL BIOLOGY-MEDICINE, RESEARCH & EXPERIMENTAL
CiteScore
26.70
自引率
1.20%
发文量
309
审稿时长
1.7 months
期刊介绍: Science Translational Medicine is an online journal that focuses on publishing research at the intersection of science, engineering, and medicine. The goal of the journal is to promote human health by providing a platform for researchers from various disciplines to communicate their latest advancements in biomedical, translational, and clinical research. The journal aims to address the slow translation of scientific knowledge into effective treatments and health measures. It publishes articles that fill the knowledge gaps between preclinical research and medical applications, with a focus on accelerating the translation of knowledge into new ways of preventing, diagnosing, and treating human diseases. The scope of Science Translational Medicine includes various areas such as cardiovascular disease, immunology/vaccines, metabolism/diabetes/obesity, neuroscience/neurology/psychiatry, cancer, infectious diseases, policy, behavior, bioengineering, chemical genomics/drug discovery, imaging, applied physical sciences, medical nanotechnology, drug delivery, biomarkers, gene therapy/regenerative medicine, toxicology and pharmacokinetics, data mining, cell culture, animal and human studies, medical informatics, and other interdisciplinary approaches to medicine. The target audience of the journal includes researchers and management in academia, government, and the biotechnology and pharmaceutical industries. It is also relevant to physician scientists, regulators, policy makers, investors, business developers, and funding agencies.
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