Rosiglitazone alleviates intrahepatic cholestasis induced by α-naphthylisothiocyanate in mice: The role of circulating 15-deoxy-Δ12,14-PGJ2 and Nogo

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 gamma, whose endogenous agonist is 15-deoxy-Delta(12,14)-PGJ(2) (15d-PGJ(2)). 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 gamma or Nogo-B knockout mice received intragastric administration of alpha-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 gamma 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-PGJ(2) but increased Nogo-B in serum, and both were corrected by rosiglitazone. Nogo-B deficiency in the liver increased 15d-PGJ(2) production, thereby activating expression of PPAR gamma 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-PGJ(2) and increased Nogo-B levels were significantly correlated with classical cholestatic markers. Conclusions and Implications Levels of 15d-PGJ(2) and Nogo are important biomarkers for intrahepatic cholestasis. Synthetic agonists of PPAR gamma could be used for treatment of intrahepatic cholestasis and cholestasis-associated dyslipidemia.