Deoxycholic acid induces intracellular signaling through membrane perturbations
Deoxycholic acid induces intracellular signaling through membrane perturbations
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DOI：
10.1074/jbc.m506710200
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发表时间：
2006-05-26
影响因子：
4.8
通讯作者：
Martinez, Jesse D.
中科院分区：
文献类型：
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作者：
Jean-Louis, Samira;Akare, Sandeep;Martinez, Jesse D.
长期以来，二级胆汁酸一直被认为是结肠肿瘤的促进剂;然而，其作用机制仍不清楚。在这项研究中，我们研究了胆汁酸在细胞膜上的作用，发现它们可以通过改变膜微区来扰乱膜结构。用甲基-β-环糊精处理膜胆固醇的耗竭抑制脱氧胆酸（DCA）诱导的细胞凋亡，并用菲律宾蛋白染色胆固醇显示DCA引起膜中这种脂质的显著重排。同样，发现DCA影响小窝蛋白-1的膜分布，小窝蛋白-1是一种在小窝膜微区富集的标记蛋白。此外，荧光各向异性显示，DCA导致膜流动性的降低与HCT 116细胞的DCA处理4小时后观察到的膜胆固醇含量的增加一致。值得注意的是，通过使用放射性标记的胆汁酸，我们发现胆汁酸能够根据其物理化学性质不同地与微区相互作用并定位于微区。DCA也被发现诱导酪氨酸磷酸化和激活受体酪氨酸激酶表皮生长因子受体在配体非依赖性的方式。相反，熊去氧胆酸没有表现出任何这些影响，即使它与微区显着相互作用。总的来说，这些数据表明，胆汁酸诱导的信号是通过改变质膜结构和胆固醇的再分布。
Secondary bile acids have long been postulated to be tumor promoters in the colon; however, their mechanism of action remains unclear. In this study, we examined the actions of bile acids at the cell membrane and found that they can perturb membrane structure by alteration of membrane microdomains. Depletion of membrane cholesterol by treating with methyl-beta-cyclodextrin suppressed deoxycholic acid (DCA)-induced apoptosis, and staining for cholesterol with filipin showed that DCA caused a marked rearrangement of this lipid in the membrane. Likewise, DCA was found to affect membrane distribution of caveolin-1, amarker protein that is enriched in caveolae membrane microdomains. Additionally, fluorescence anisotropy revealed that DCA causes a decrease in membrane fluidity consistent with the increase in membrane cholesterol content observed after 4 h of DCA treatment of HCT116 cells. Significantly, by using radiolabeled bile acids, we found that bile acids are able to interact with and localize to microdomains differently depending on their physicochemical properties. DCA was also found to induce tyrosine phosphorylation and activate the receptor tyrosine kinase epidermal growth factor receptor in a ligand-independent manner. In contrast, ursodeoxycholic acid did not exhibit any of these effects even though it interacted significantly with the microdomains. Collectively, these data suggest that bile acid-induced signaling is initiated through alterations of the plasma membrane structure and the redistribution of cholesterol.