Metabolomic Analysis Reveals the Therapeutic Effects of MBT1805, a Novel Pan-Peroxisome Proliferator-Activated Receptor Agonist, on α-Naphthylisothiocyanate-Induced Cholestasis in Mice

Chang Wang; Fei Peng; Bohua Zhong; Ying Shi; Xiaomei Wang; Xueyuan Jin; Junqi Niu

doi:10.3389/fphar.2021.732478

Metabolomic Analysis Reveals the Therapeutic Effects of MBT1805, a Novel Pan-Peroxisome Proliferator-Activated Receptor Agonist, on α-Naphthylisothiocyanate-Induced Cholestasis in Mice

Front Pharmacol. 2021 Oct 29:12:732478. doi: 10.3389/fphar.2021.732478. eCollection 2021.

Authors

Chang Wang^{1

2}, Fei Peng^{1

2}, Bohua Zhong³, Ying Shi^{1

2}, Xiaomei Wang^{1

2}, Xueyuan Jin⁴, Junqi Niu^{1

2}

Affiliations

¹ Department of Hepatology, The First Hospital of Jilin University, Changchun, Jilin, China.
² Key Laboratory of Zoonosis Research, Ministry Education, Changchun, Jilin, China.
³ Beijing JK HuaYuan Med Tech Company LTD, Beijing, China.
⁴ International Center for Liver Disease Treatment, Fifth Medical Center of China PLA General Hospital, Beijing, China.

Abstract

Background and Aims: 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. Methods: 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. Results: 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. Conclusions: MBT1805 is a potential candidate drug for cholestasis, with a balanced PPARα/γ/δ activation effect.

Keywords: MBT1805; agonist; cholestasis; peroxisome proliferator-activated receptor; α-naphthylisothiocyanate.