METHODS: We studied the relationship between MCJ and cholestasis-induced liver injury in liver biopsies from patients with chronic cholestatic liver diseases, and in livers and primary hepatocytes obtained from WT and MCJ-KO mice. Bile duct ligation (BDL) was used as an animal model of cholestasis, and primary hepatocytes were treated with toxic doses of bile acids. We evaluated the effect of MCJ silencing for the treatment of cholestasis-induced liver injury.
RESULTS: Elevated levels of MCJ were detected in the liver tissue of patients with chronic cholestatic liver disease when compared with normal liver tissue. Likewise, in mouse models, the hepatic levels of MCJ were increased. After BDL, MCJ-KO animals showed significantly decreased inflammation and apoptosis. In an in vitro model of bile-acid induced toxicity, we observed that the loss of MCJ protected mouse primary hepatocytes from bile acid-induced mitochondrial ROS overproduction and ATP depletion, enabling higher cell viability. Finally, the in vivo inhibition of the MCJ expression, following BDL, showed reduced liver injury and a mitigation of the main cholestatic characteristics.
CONCLUSIONS: We demonstrated that MCJ is involved in the progression of cholestatic liver injury, and our results identified MCJ as a potential therapeutic target to mitigate the liver injury caused by cholestasis.
BACKGROUND: In this study, we examine the effect of mitochondrial respiratory chain inhibition by MCJ on bile acid-induced liver toxicity. The loss of MCJ protects hepatocytes against apoptosis, mitochondrial ROS overproduction, and ATP depletion as a result of bile acid toxicity. Our results identify MCJ as a potential therapeutic target to mitigate liver injury in cholestatic liver diseases.
■我们研究了MCJ与慢性胆汁淤积性肝病患者肝活检中胆汁淤积性肝损伤之间的关系,以及从WT和MCJ-KO小鼠获得的肝脏和原代肝细胞。胆管结扎(BDL)作为胆汁淤积的动物模型,和原代肝细胞用毒性剂量的胆汁酸处理。我们评估了MCJ沉默治疗胆汁淤积诱导的肝损伤的效果。
■与正常肝组织相比,在慢性胆汁淤积性肝病患者的肝组织中检测到MCJ水平升高。同样,在老鼠模型中,肝脏MCJ水平升高。BDL之后,MCJ-KO动物表现出显著降低的炎症和凋亡。在胆汁酸诱导毒性的体外模型中,我们观察到,MCJ的损失保护小鼠原代肝细胞从胆汁酸诱导的线粒体ROS过度产生和ATP耗竭,使更高的细胞活力。最后,MCJ表达的体内抑制,在BDL之后,显示出减少的肝损伤和缓解的主要胆汁淤积特征。
■我们证明MCJ参与胆汁淤积性肝损伤的进展,我们的结果确定MCJ是减轻胆汁淤积引起的肝损伤的潜在治疗靶点。
■在这项研究中,我们研究了MCJ抑制线粒体呼吸链对胆汁酸诱导的肝毒性的影响。MCJ的丢失保护肝细胞免受凋亡,线粒体ROS过度生产,和ATP消耗作为胆汁酸毒性的结果。我们的结果确定MCJ是缓解胆汁淤积性肝病中肝损伤的潜在治疗靶点。