Bile acid induces hydrophobicity-dependent membrane alterations

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.