Wang Chang, Peng Fei, Zhong Bohua, Shi Ying, Wang Xiaomei, Jin Xueyuan, Niu Junqi
Department of Hepatology, The First Hospital of Jilin University, Changchun, Jilin, China.
Key Laboratory of Zoonosis Research, Ministry Education, Changchun, Jilin, China.
Front Pharmacol. 2021 Oct 29;12:732478. doi: 10.3389/fphar.2021.732478. eCollection 2021.
Therapeutic drugs that are used to treat cholestatic liver disease are limited; however, the results of clinical trials on primary biliary cholangitis treatment targeting peroxisome proliferator-activated receptors (PPARs) are encouraging. In this study, we aimed to identify the effects of MBT1805, a novel balanced PPARα/γ/δ agonist, on cholestasis induced by α-naphthylisothiocyanate (ANIT) and elucidate the underlying mechanisms through untargeted and bile acid-targeted metabolomic analysis. Levels of serum biochemical indicators (transaminase, aspartate transaminase, alkaline phosphatase, and total bilirubin) and liver histopathology were analyzed to evaluate the therapeutic effects of MBT1805 on ANIT-induced cholestasis in C57BL/6 mice. Untargeted and bile acid-targeted metabolomic analysis of liver tissues was performed using ultrahigh-performance liquid chromatography-triple quadrupole mass spectrometry (UPLC-MC/MC). qRT-PCR and Western blot analysis were carried out to measure the expression of key enzymes and transporters regulating bile acid synthesis, biotransformation, and transport. MBT1805 significantly improved abnormal levels of liver biochemical indicators and gallbladder enlargement induced by ANIT. Histopathological analysis showed that MBT1805 effectively relieved ANIT-induced necrosis, vacuolation, and inflammatory infiltration. Untargeted metabolomic analysis identified 27 metabolites that were involved in the primary biliary acid biosynthesis pathway. In addition, bile acid-targeted metabolomics showed that MBT1805 could alleviate the abnormal bile acid content and composition induced by ANIT. Furthermore, qRT-PCR and Western blot results confirmed that MBT1805 could effectively regulate bile acid synthesis, biotransformation, and transport which helps relieve cholestasis. MBT1805 is a potential candidate drug for cholestasis, with a balanced PPARα/γ/δ activation effect.
用于治疗胆汁淤积性肝病的治疗药物有限；然而，针对过氧化物酶体增殖物激活受体（PPARs）的原发性胆汁性胆管炎治疗的临床试验结果令人鼓舞。在本研究中，我们旨在确定新型平衡PPARα/γ/δ激动剂MBT1805对α-萘异硫氰酸酯（ANIT）诱导的胆汁淤积的影响，并通过非靶向和胆汁酸靶向代谢组学分析阐明其潜在机制。分析血清生化指标（转氨酶、天冬氨酸转氨酶、碱性磷酸酶和总胆红素）水平及肝脏组织病理学，以评估MBT1805对C57BL/6小鼠ANIT诱导的胆汁淤积的治疗效果。使用超高效液相色谱-三重四极杆质谱（UPLC-MC/MC）对肝脏组织进行非靶向和胆汁酸靶向代谢组学分析。进行qRT-PCR和蛋白质印迹分析以测量调节胆汁酸合成、生物转化和转运的关键酶和转运蛋白的表达。MBT1805显著改善了ANIT诱导的肝脏生化指标异常和胆囊肿大。组织病理学分析表明，MBT1805有效缓解了ANIT诱导的坏死、空泡化和炎症浸润。非靶向代谢组学分析鉴定出27种参与初级胆汁酸生物合成途径的代谢物。此外，胆汁酸靶向代谢组学表明，MBT1805可以减轻ANIT诱导的胆汁酸含量和组成异常。此外，qRT-PCR和蛋白质印迹结果证实，MBT1805可以有效调节胆汁酸合成、生物转化和转运，这有助于缓解胆汁淤积。MBT1805是一种具有平衡PPARα/γ/δ激活作用的胆汁淤积潜在候选药物。
