TY - JOUR
T1 - Bile acid induces hydrophobicity-dependent membrane alterations
AU - Akare, Sandeep
AU - Martinez, Jesse D.
N1 - Funding Information:
This work was supported by the National Institutes of Health Grant PO1 CA-72008.
PY - 2005/6/15
Y1 - 2005/6/15
N2 - 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 PKCα activation and cholesterol up-regulation as model indicators. We found that bile acid-induced PKCα activation is a function of hydrophobicity and correlated with alteration in membrane lipid composition, as evident by the significant up-regulation in membrane cholesterol and phospholipid. We found that bile acid do not cause cell membrane disruption at a concentration sufficient to activate PKCα, but do induce drastic alterations in membrane composition. Bile acid also induced the modification and up-regulation of caveolin-1 in a hydrophobicity-dependent manner, implying widespread receptor dysregulation. 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.
AB - 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 PKCα activation and cholesterol up-regulation as model indicators. We found that bile acid-induced PKCα activation is a function of hydrophobicity and correlated with alteration in membrane lipid composition, as evident by the significant up-regulation in membrane cholesterol and phospholipid. We found that bile acid do not cause cell membrane disruption at a concentration sufficient to activate PKCα, but do induce drastic alterations in membrane composition. Bile acid also induced the modification and up-regulation of caveolin-1 in a hydrophobicity-dependent manner, implying widespread receptor dysregulation. 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.
KW - Bile acid hydrophobicity
KW - Caveolin
KW - Cholesterol
KW - Colon cancer
KW - Membrane alteration
KW - PKCα
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U2 - 10.1016/j.bbalip.2005.04.006
DO - 10.1016/j.bbalip.2005.04.006
M3 - Article
C2 - 15951237
AN - SCOPUS:20444471137
SN - 1388-1981
VL - 1735
SP - 59
EP - 67
JO - Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids
JF - Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids
IS - 1
ER -