Dataset Information

Rosiglitazone alleviates intrahepatic cholestasis induced by ?-naphthylisothiocyanate in mice: The role of circulating 15-deoxy-?^12,14 -PGJ₂ and Nogo.

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 PPAR?, whose endogenous agonist is 15-deoxy-?^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 PPAR? or Nogo-B knockout mice received intragastric administration of ?-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 PPAR? 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 PPAR? 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 PPAR? could be used for treatment of intrahepatic cholestasis and cholestasis-associated dyslipidemia.

SUBMITTER: Zhang S

PROVIDER: S-EPMC7042110 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Publications

Rosiglitazone alleviates intrahepatic cholestasis induced by α-naphthylisothiocyanate in mice: The role of circulating 15-deoxy-Δ<sup>12,14</sup> -PGJ<sub>2</sub> and Nogo.

Zhang Shuang S Yu Miao M Guo Fangling F Yang Xiaoxiao X Chen Yuanli Y Ma Chuanrui C Li Qi Q Wei Zhuo Z Li Xiaoju X Wang Hua H Hu Huaqing H Zhang Yujue Y Kong Derun D Miao Qing Robert QR Hu Wenquan W Hajjar David P DP Zhu Yan Y Han Jihong J Duan Yajun Y

British journal of pharmacology 20200203 5

<h4>Background and purpose</h4>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<sup>12,14</sup> -PGJ<sub>2</sub> (15d-PGJ<sub>2</sub> ). 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.<h4>Experimental ap ...[more]

PMID: 31658492

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