FXR and TGR5 Agonists Ameliorate Liver Injury, Steatosis, and Inflammation After Binge or Prolonged Alcohol Feeding in Mice.
FXR and TGR5 Agonists Ameliorate Liver Injury, Steatosis, and Inflammation After Binge or Prolonged Alcohol Feeding in Mice.
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DOI：
10.1002/hep4.1256
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发表时间：
2018-11
影响因子：
5.1
通讯作者：
Szabo G
中科院分区：
文献类型：
--
作者：
Iracheta-Vellve A;Calenda CD;Petrasek J;Ambade A;Kodys K;Adorini L;Szabo G
胆汁酸（BA）激活各种专用受体，包括法尼醇X受体（FXR）和武田G蛋白偶联受体5（TGR 5）。FXR激动剂奥贝胆酸（OCA）被批准用于治疗原发性胆汁性胆管炎，并在NASH患者中显示出有希望的结果，而TGR 5激动剂靶向炎症和代谢。我们假设FXR和/或TGR 5激动剂可能对小鼠早期酒精性肝病（ALD）有治疗作用，其中肝脏炎症起主要作用。OCA、INT-777和INT-767是BA衍生物，分别对FXR、TGR 5或两者具有选择性激动剂特性。这些化合物在两种早期ALD小鼠模型（3天暴食模型和延长Lieber DeCarli饮食12天）中进行了测试。使用血清丙氨酸转氨酶和肝组织学评估肝损伤，使用肝切片油红O染色评估脂肪变性，使用真实的实时聚合酶链反应评估基因表达的变化。在乙醇狂欢模型中，OCA和INT-777给药可减少肝大泡性脂肪变性，并保护其免受乙醇诱导的肝损伤。在长期乙醇给药后，OCA、INT-767或INT-777处理的小鼠显示肝脂肪变性减少，与肝脂肪酸合成酶蛋白表达减少相关，并保护肝损伤。在乙醇给药的两种模型中，BA受体激动剂治疗调节了脂肪生成基因表达，并降低了肝脏白细胞介素-1 β mRNA表达，这与通过环磷酸腺苷诱导的蛋白激酶A激活增加的NLRP 3炎性体泛素化有关。结论：OCA、INT-767或INT-777给药可有效减少小鼠中急性和慢性乙醇诱导的脂肪变性和炎症，疗效程度取决于乙醇给药的持续时间，表明FXR和TGR 5激活均可保护ALD模型免受肝损伤。
Bile acids (BAs) activate various dedicated receptors, including the farnesoid X receptor (FXR) and the Takeda G protein‐coupled receptor 5 (TGR5). The FXR agonist obeticholic acid (OCA) is licensed for the treatment of primary biliary cholangitis and has shown promising results in NASH patients, whereas TGR5 agonists target inflammation and metabolism. We hypothesized that FXR and/or TGR5 agonists may be therapeutic in early alcoholic liver disease (ALD) in mice, in which hepatic inflammation plays a major role. OCA, INT‐777, and INT‐767 are BA derivatives with selective agonist properties for FXR, TGR5, or both, respectively. These compounds were tested in two mouse models (3‐day binge model and prolonged Lieber DeCarli diet for 12 days) of early ALD. Serum alanine aminotransferase and liver histology were used to assess liver injury, Oil Red O staining of liver sections to assess steatosis, and real‐time polymerase chain reaction to assess changes in gene expression. In the ethanol binge model, treatment with OCA and INT‐777 decreased hepatic macrovesicular steatosis and protected from ethanol‐induced liver injury. After prolonged ethanol administration, mice treated with OCA, INT‐767, or INT‐777 showed decreased hepatic steatosis, associated with reduced liver fatty acid synthase protein expression, and protection from liver injury. Treatment with BA receptor agonists in both models of ethanol administration modulated lipogenic gene expression, and decreased liver interleukin‐1β mRNA expression associated with increased ubiquitination of NLRP3 inflammasome through cyclic adenosine monophosphate–induced activation of protein kinase A. Conclusion: OCA, INT‐767, or INT‐777 administration is effective in reducing acute and chronic ethanol‐induced steatosis and inflammation in mice, with varying degrees of efficacy depending on the duration of ethanol administration, indicating that both FXR and TGR5 activation can protect from liver injury in ALD models.
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发表时间：
2008-10
期刊：
Hepatology (Baltimore, Md.)
影响因子：
--
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Hritz I;Mandrekar P;Velayudham A;Catalano D;Dolganiuc A;Kodys K;Kurt-Jones E;Szabo G
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