Rosiglitazone alleviates intrahepatic cholestasis induced by α‐naphthylisothiocyanate in mice: The role of circulating 15‐deoxy‐Δ12, 14‐PGJ2 and Nogo. (3rd February 2020)

• Record Type: Journal Article
• Authors: Zhang, Shuang; Yu, Miao; Guo, Fangling; Yang, Xiaoxiao; Chen, Yuanli; Ma, Chuanrui; Li, Qi; Wei, Zhuo; Li, Xiaoju; Wang, Hua; Hu, Huaqing; Zhang, Yujue; Kong, Derun; Miao, Qing Robert; Hu, Wenquan; Hajjar, David P.; Zhu, Yan; Han, Jihong; Duan, Yajun
• Is Part Of: British journal of pharmacology. Volume 177:Number 5(2020)
• Page Start: 1041
• Page End: 1060
• Publication Date: 2020-02-03
• Subjects: Pharmacology -- Periodicals; Chemotherapy -- Periodicals; Drug Therapy -- Periodicals; Pharmacology -- Periodicals; 615.1
• DOI: 10.1111/bph.14886
• Languages: English
• ISSNs: 0007-1188

Abstract

Abstract : Background and Purpose: Intrahepatic cholestasis is mainly caused by dysfunction of bile secretion and has limited effective treatment. Rosiglitazone is a synthetic agonist of PPARγ, whose endogenous agonist is 15‐deoxy‐Δ 12, 14 ‐PGJ2 (15d‐PGJ2 ). Reticulon 4B (Nogo‐B) is the detectable Nogo protein family member in the liver and secreted into circulation. Here, we determined if rosiglitazone can alleviate intrahepatic cholestasis in mice. Experimental Approach: Wild‐type, hepatocyte‐specific PPARγ or Nogo‐B knockout mice received intragastric administration of α‐naphthylisothiocyanate (ANIT) and/or rosiglitazone, followed by determination of intrahepatic cholestasis and the involved mechanisms. Serum samples from primary biliary cholangitis (PBC) patients and non‐PBC controls were analysed for cholestasis‐related parameters. Key Results: Rosiglitazone prevented wild type, but not hepatocyte‐specific PPARγ deficient mice from developing ANIT‐induced intrahepatic cholestasis by increasing expression of bile homeostatic proteins, reducing hepatic necrosis, and correcting abnormal serum parameters and enterohepatic circulation of bile. Nogo‐B knockout provided protection similar to that of rosiglitazone treatment. ANIT‐induced intrahepatic cholestasis decreased 15d‐PGJ2 but increased Nogo‐B in serum, and both were corrected by rosiglitazone. Nogo‐B deficiency in the liver increased 15d‐PGJ2 production, thereby activating expression of PPARγ and bile homeostatic proteins. Rosiglitazone and Nogo‐B deficiency also alleviated cholestasis‐associated dyslipidemia. In addition, rosiglitazone reduced symptoms of established intrahepatic cholestasis in mice. In serum from PBC patients, the decreased 15d‐PGJ2 and increased Nogo‐B levels were significantly correlated with classical cholestatic markers. Conclusions and Implications: Levels of 15d‐PGJ2 and Nogo are important biomarkers for intrahepatic cholestasis. Synthetic agonists of PPARγ could be used for treatment of intrahepatic cholestasis and cholestasis‐associated dyslipidemia.