Shuang Zhang1, Miao Yu2, Fangling Guo1, Xiaoxiao Yang3, Yuanli Chen3, Chuanrui Ma1, Qi Li1, Zhuo Wei1, Xiaoju Li1, Hua Wang4, Huaqing Hu4, Yujue Zhang4, Derun Kong4, Qing Robert Miao5, Wenquan Hu5, David P Hajjar6, Yan Zhu7, Jihong Han1,3, Yajun Duan3. 1. College of Life Sciences, Key Laboratory of Bioactive Materials of Ministry of Education, State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin, China. 2. Institute for Cardiovascular Science and Department of Cardiovascular Surgery of the First Affiliated Hospital, Medical College of Soochow University, Suzhou, China. 3. Key Laboratory of Metabolism and Regulation for Major Diseases of Anhui Higher Education Institutes, College of Food and Biological Engineering, Hefei University of Technology, Hefei, China. 4. Department of Oncology, First Affiliated Hospital of Anhui Medical University, Hefei, China. 5. Winthrop Hospital Diabetes and Obesity Research Center, New York University, New York, New York. 6. Weill Cornell Medicine, Cornell University, New York, New York. 7. Tianjin State Key Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China.
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-Δ12,14 -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.
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-Δ12,14 -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.
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