Osteopontin Deficiency Alters Biliary Homeostasis and Protects against Gallstone Formation.
Osteopontin Deficiency Alters Biliary Homeostasis and Protects against Gallstone Formation.
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骨桥蛋白缺乏会改变胆道稳态并防止胆结石形成
DOI：
10.1038/srep30215
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发表时间：
2016-08-03
影响因子：
4.6
通讯作者：
Chen JH
中科院分区：
文献类型：
--
作者：
Lin J;Lu M;Shao WQ;Chen ZY;Zhu WW;Lu L;Jia HL;Cai D;Qin LX;Chen JH
过量胆汁胆固醇沉淀为固体晶体是胆固醇结石形成的先决条件，胆固醇结石的形成是由于胆汁内稳态紊乱所致。胆汁稳态由肝细胞中复杂的基因网络调节。如果不加管理，胆固醇晶体将聚集、融合并形成胆结石。我们以前观察到胆结石患者胆汁和胆囊中骨桥蛋白（OPN）水平降低。然而，肝脏OPN在胆固醇结石形成中的作用和机制尚未确定。在这项研究中，我们发现，肝OPN的表达增加，胆囊结石患者相比，胆囊结石的同行。然后，我们观察到OPN缺陷小鼠比野生型小鼠更不易于胆固醇结石形成。进一步的机制研究表明，这种保护作用与胆汁成分的改变有关，是由肝脏CYP 7A 1表达增加和肝脏SHP、ATP 8B 1、SR-B1和SREBP-2表达减少引起的。最后，在胆囊结石患者中，肝脏OPN的表达与这些肝脏基因的表达之间的相关性被验证。总之，我们的研究结果表明，肝脏OPN通过调节胆汁代谢促进胆固醇结石形成，并可能被开发为胆结石治疗的治疗靶点。
The precipitation of excess biliary cholesterol as solid crystals is a prerequisite for cholesterol gallstone formation, which occurs due to disturbed biliary homeostasis. Biliary homeostasis is regulated by an elaborate network of genes in hepatocytes. If unmanaged, the cholesterol crystals will aggregate, fuse and form gallstones. We have previously observed that the levels of osteopontin (OPN) in bile and gallbladder were reduced in gallstone patients. However, the role and mechanism for hepatic OPN in cholesterol gallstone formation is undetermined. In this study, we found that the expression of hepatic OPN was increased in gallstone patients compared with gallstone-free counterparts. Then, we observed that OPN-deficient mice were less vulnerable to cholesterol gallstone formation than wild type mice. Further mechanistic studies revealed that this protective effect was associated with alterations of bile composition and was caused by the increased hepatic CYP7A1 expression and the reduced expression of hepatic SHP, ATP8B1, SR-B1 and SREBP-2. Finally, the correlations between the expression of hepatic OPN and the expression of these hepatic genes were validated in gallstone patients. Taken together, our findings reveal that hepatic OPN contributes to cholesterol gallstone formation by regulating biliary metabolism and might be developed as a therapeutic target for gallstone treatments.