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 PKCalpha activation and cholesterol up-regulation as model indicators. We found that bile acid-induced PKCalpha 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 PKCalpha, 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.
Akare
Sandeep
S
Arizona Cancer Center, Department of Cell Biology and Anatomy, University of Arizona, 1515 N. Campbell Avenue, Tucson, Arizona 85724, United States.
Martinez
Jesse D
JD
D001647:Bile Acids and Salts / Q000737:chemistry* / Q000494:pharmacology*; D015415:Biomarkers; D018938:Caco-2 Cells; D051242:Caveolin 1; D022461:Caveolins / Q000378:metabolism; D002462:Cell Membrane / Q000187:drug effects* / Q000378:metabolism*; D002784:Cholesterol / Q000378:metabolism; D002788:Cholesterol Esters / Q000737:chemistry / Q000494:pharmacology; D003840:Deoxycholic Acid / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D010743:Phospholipids / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011493:Protein Kinase C / Q000378:metabolism; D051571:Protein Kinase C-alpha; D021381:Protein Transport / Q000187:drug effects; D012521:Sarcosine / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D015398:Signal Transduction
D001647:Bile Acids and Salts; D015415:Biomarkers; C495540:CAV1 protein, human; D051242:Caveolin 1; D022461:Caveolins; D002788:Cholesterol Esters; D010743:Phospholipids; D003840:Deoxycholic Acid; D002784:Cholesterol; D007770:L-Lactate Dehydrogenase; C496628:PRKCA protein, human; D011493:Protein Kinase C; D051571:Protein Kinase C-alpha; D048049:Extracellular Signal-Regulated MAP Kinases; C013440:cholesteryl succinate; D012521:Sarcosine