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 (CCl 4 )–, 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.

中文翻译：

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抑制血红素硫代酸单加氧酶 CYP1B1 通过积累海藻糖来防止肝星状细胞活化和肝纤维化


产生细胞外基质的肝星状细胞 （HSC） 的激活是肝纤维化的关键事件。我们发现血红素硫代酸单加氧酶细胞色素 P450 1B1 （CYP1B1） 的表达在人和小鼠纤维化肝脏中升高并激活了 HSC。CYP1B1 的全身或 HSC 特异性消融和药理抑制减弱了 HSC 活化，并保护雄性而不是雌性小鼠免受硫代乙酰胺 （TAA） – 、四氯化碳 （CCl 4 ） – 或胆管结扎 （BDL） 诱导的肝纤维化。代谢组学分析显示，由于肠道抑制海藻糖代谢酶海藻糖，CYP1B1 缺陷型 HSC 中双糖海藻糖增加，我们发现其基因是 RARα 的靶标。海藻糖或其抗水解衍生物乳糖通过作为 HSC 特异性自噬抑制剂在体外和体内表现出有效的抗纤维化活性，这可能是 CYP1B1 抑制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，由肝肠串扰和海藻糖介导。在翻译水平上，CYP1B1 的药理学抑制或使用海藻糖/乳糖可能代表肝纤维化的治疗策略。