Bile acid induces hydrophobicity-dependent membrane alterations
Bile acid induces hydrophobicity-dependent membrane alterations
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DOI：
10.1016/j.bbalip.2005.04.006
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发表时间：
2005-06-15
影响因子：
4.8
通讯作者：
Martinez, JD
中科院分区：
文献类型：
--
作者：
Akare, S;Martinez, JD
由于细胞信号的改变，粪胆汁酸浓度升高是结肠癌的已知危险因素。在胆汁酸摄取最少的结肠细胞中，疏水诱导的膜扰动和改变已被提出，但这些膜改变在很大程度上未被表征。在这项研究中，我们研究了胆汁酸诱导的膜改变的决定因素和特征，利用PKC α激活和胆固醇上调作为模型指标。我们发现胆汁酸诱导的PKC α活化是一种疏水性功能，与膜脂组成的改变有关，这一点可以从膜胆固醇和磷脂的显著上调中得到证明。我们发现胆汁酸在足以激活PKC α的浓度下不会引起细胞膜破坏，但确实会引起膜成分的剧烈改变。胆囊酸还以疏水性依赖的方式诱导小洞蛋白-1的修饰和上调，这意味着广泛的受体失调。同样，ERK1/2的激活仅在疏水胆汁酸的反应中被观察到，这表明疏水诱导的腔泡或膜应激。对十二烷基肌氨酸钠和半琥珀酸胆固醇的实验表明，胆汁酸诱导的膜改变可以被与胆汁酸无关的疏水分子模拟，这强烈暗示疏水性是胆汁酸信号传导的重要决定因素。(c) 2005 Elsevier b.v.版权所有
Elevated concentrations of fecal bile acids are a known risk factor for colon cancer, owing to alterations in cellular signaling. In colonic cells, where bile acid uptake is minimal, the hydrophobicity-induced membrane perturbation and alterations have been proposed, but these membrane alterations are largely uncharacterized. In this study, we examined the determinants and characteristics of bile acid-induced membrane alterations, utilizing PKC alpha activation and cholesterol up-regulation as model indicators. We found that bile acid-induced PKC alpha activation is a function of hydrophobicity and correlated with alteration in membrane lipid composition, as evident by the significant upregulation in membrane cholesterol and phospholipid. We found that bile acid do not cause cell membrane disruption at a concentration sufficient to activate PKC alpha, but do induce drastic alterations in membrane composition. Bile acid also induced the modification and upregulation of caveolin-1 in a hydrophobicity-dependent manner, implying widespread receptor dygregulation. Similarly, ERK1/2 activation was observed only in response to hydrophobic bile acids, suggesting hydrophobicity-induced caveolar or membrane stress. Experiments with sodium lauryl sarcosine and cholesteryl hemisuccinate showed that bile acid-induced membrane alterations can be mimicked by hydrophobic molecules unrelated to bile acids, strongly implicating hydrophobicity as an important determinant of bile acid signaling. (c) 2005 Elsevier B.V All rights reserved.