Rosiglitazone alleviates intrahepatic cholestasis induced by alpha-naphthylisothiocyanate in mice: The role of circulating 15-deoxy-Delta(12,14)-PGJ(2) and Nogo
Rosiglitazone alleviates intrahepatic cholestasis induced by alpha-naphthylisothiocyanate in mice: The role of circulating 15-deoxy-Delta(12,14)-PGJ(2) and Nogo
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罗格列酮减轻小鼠α-萘基异硫氰酸酯诱导的肝内胆汁淤积：循环15-脱氧-Delta(12,14)-PGJ(2)和Nogo的作用
DOI：
10.1111/bph.14886
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发表时间：
2020
影响因子：
7.3
通讯作者：
Duan Yajun
中科院分区：
文献类型：
--
作者：
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
背景与目的肝内胆汁淤积症（IntrahepaticCholestasis，IchS）主要是由于胆汁分泌功能障碍所致，目前治疗效果有限。罗格列酮是一种合成的PPARγ激动剂，其内源性激动剂是15-脱氧-Δ 12，14-PGJ 2（15 d-PGJ 2）。Reticulon 4 B（Nogo B）是肝脏中可检测到的Nogo蛋白家族成员，并分泌到循环中。实验方法野生型、肝细胞特异性PPARγ或Nogo-B基因敲除小鼠接受α-萘异硫氰酸酯（ANIT）和/或罗格列酮灌胃给药，然后测定肝内胆汁淤积及其相关机制。对原发性胆管炎（PBC）患者和非PBC对照的血清样本进行胆汁淤积相关参数分析。Key Results罗格列酮通过增加胆汁稳态蛋白的表达、减少肝坏死、纠正异常血清参数和胆汁的肝肠循环，阻止野生型小鼠发生ANIT诱导的肝内胆汁淤积，但不能阻止肝细胞特异性PPARγ缺陷小鼠发生ANIT诱导的肝内胆汁淤积。Nogo B基因敲除提供了与罗格列酮治疗相似的保护作用。ANIT诱导的肝内胆汁淤积降低血清中15 d-PGJ 2，但增加Nogo-B，罗格列酮可纠正这两种情况。肝脏中Nogo B缺乏增加了15 d-PGJ 2的产生，从而激活了PPARγ和胆汁稳态蛋白的表达。罗格列酮和Nogo B缺乏也可缓解胆汁淤积相关血脂异常。此外，罗格列酮还能减轻小鼠肝内胆汁淤积症的症状。PBC患者血清中15 d-PGJ 2水平降低和Nogo-B水平升高与经典胆汁淤积标志物显著相关。结论15 d-PGJ 2和Nogo水平是肝内胆汁淤积的重要标志物。合成的PPARγ激动剂可用于治疗肝内胆汁淤积和胆汁淤积相关血脂异常。
Background and PurposeIntrahepatic 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 ApproachWild‐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 ResultsRosiglitazone 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‐PGJ2but increased Nogo‐B in serum, and both were corrected by rosiglitazone. Nogo‐B deficiency in the liver increased 15d‐PGJ2production, 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‐PGJ2and increased Nogo‐B levels were significantly correlated with classical cholestatic markers.Conclusions and ImplicationsLevels of 15d‐PGJ2and Nogo are important biomarkers for intrahepatic cholestasis. Synthetic agonists of PPARγ could be used for treatment of intrahepatic cholestasis and cholestasis‐associated dyslipidemia.