Hepatoprotection by the farnesoid X receptor agonist GW4064 in rat models of intra- and extrahepatic cholestasis
Hepatoprotection by the farnesoid X receptor agonist GW4064 in rat models of intra- and extrahepatic cholestasis
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DOI：
10.1172/jci200318945
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发表时间：
2003-12-01
影响因子：
15.9
通讯作者：
Jones, SA
中科院分区：
文献类型：
--
作者：
Liu, YP;Binz, J;Jones, SA
Farnesoid X受体（FXR）是一种胆汁酸激活的转录因子，是核激素受体超家族的成员。fxr缺失小鼠表现出与Byler病（一种遗传性胆汁淤积性肝病）相似的表型。在肝脏中，FXR的激活诱导了促进胆汁酸清除的转运体基因的转录，并抑制了胆汁酸生物合成的相关基因。我们研究了合成的FXR激动剂GW4064是否对肝外和肝内胆汁淤积大鼠模型中的胆汁淤积性肝损伤具有保护作用。在胆管结扎和α -萘基异硫氰酸酯模型中，GW4064治疗导致血清丙氨酸转氨酶、天冬氨酸转氨酶和乳酸脱氢酶以及其他肝损伤标志物显著降低。接受GW4064治疗的大鼠的坏死发生率和程度也有所降低，炎症细胞浸润减少，胆管增殖减少。对gw4064处理的胆汁淤血大鼠肝脏中基因表达的分析显示，胆汁酸生物合成基因的表达减少，胆汁酸转运相关基因的表达增加，包括磷脂翻转酶MDR2。合成FXR激动剂在这些动物模型中观察到的肝保护作用表明，FXR激动剂可能有助于治疗胆汁淤积性肝病。
Farnesoid X receptor (FXR) is a bile acid-activated transcription factor that is a member of the nuclear hormone receptor superfamily. Fxr-null mice exhibit a phenotype similar to Byler disease, an inherited cholestatic liver disorder. In the liver, activation of FXR induces transcription of transporter genes involved in promoting bile acid clearance and represses genes involved in bile acid biosynthesis. We investigated whether the synthetic FXR agonist GW4064 could protect against cholestatic liver damage in rat models of extrahepatic and intrahepatic cholestasis. In the bile duct-ligation and alpha-naphthylisothiocyanate models of cholestasis, GW4064 treatment resulted in significant reductions in serum alanine aminotransferase, aspartate aminotransferase, and lactate dehydrogenase, as well as other markers of liver damage. Rats that received GW4064 treatment also had decreased incidence and extent of necrosis, decreased inflammatory cell infiltration, and decreased bile duct proliferation. Analysis of gene expression in livers from GW4064-treated cholestatic rats revealed decreased expression of bile acid biosynthetic genes and increased expression of genes involved in bile acid transport, including the phospholipid flippase MDR2. The hepatoprotection seen in these animal models by the synthetic FXR agonist suggests FXR agonists may be useful in the treatment of cholestatic liver disease.