Rosiglitazone alleviates intrahepatic cholestasis induced by α-naphthylisothiocyanate in mice: The role of circulating 15-deoxy-Δ12,14 -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 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.