Bile Acids Modulate Signaling by Functional Perturbation of Plasma Membrane Domains

Abstract

Background: Bile acids (BAs) affect cellular membranes. Results: BAs stabilize domains in plasma membranes, leading to reorganization of membrane proteins and signaling perturbations. Conclusion: BAs affect cell function by modulating the stability of plasma membrane nanodomains. Significance: These results suggest mechanisms for regulation of functional membrane domains and nonreceptor-mediated BA signaling.

Deoxycholic acid modulates cell death signaling through changes in mitochondrial membrane properties

“…2F , 3F ), suggesting that effi cient cellular mechanisms are present to compensate for this effect. Such compensatory mechanisms were also previously observed when cytotoxic bile acids induced a much larger impact on isolated GPMVs than on the plasma membrane of living cells ( 17 ). Although we cannot totally exclude an effect of bile acids on very specifi c plasma membrane components, these results strongly suggest that nonspecifi c changes in plasma membrane biophysical properties are not the mechanism through which DCA induces apoptosis in healthy hepatocytes.…”

“…Interestingly, this effect was much less effi cient in the Chol-rich liquid-ordered phase ( l o ), possibly as a consequence of a lower affi nity of the bile acids toward more ordered membranes (14)(15)(16). This was also recently confi rmed in giant plasma membrane vesicles (GPMVs) isolated from rat tumor mast cells ( 17 ). The authors have suggested that DCA might interfere with the organization of signaling proteins due to its membrane-disordering effect.…”

“…Cytotoxic bile acids have been shown to induce cell death through multiple pathways, depending on their concentrations ( 3,4 ), but the corresponding mechanism of action of these molecules is still highly ambiguous and a matter of much debate, as the target of these molecules has recently been alternatively suggested to be the plasma membrane ( 17 ) or the MOM ( 20 ). Our previous studies have demonstrated that at physiologically active concentrations, cytotoxic bile acids have the potential to modulate the structure of lipid membranes, but only for certain lipidic compositions, namely, in the presence of low concentrations of Chol ( 14 ).…”

“…The product of the difference from the mean (PDM) and Pearson's correlation coefficient ( R r ) ( 27 ) parameters were obtained through WCIF ImageJ (http://www.uhnresearch.ca/facilities/ wcif/imagej/). ( 14,17 ) have confi rmed that apoptosis-inducing bile acids are able to modulate lipid membrane fl uidity, suggesting that their physiological activity could be associated with this effect. Different organelles have been anticipated as targets for cytotoxic bile acids, namely, the plasma membrane ( 17 ) and the mitochondria ( 20 ).…”

“…( 14,17 ) have confi rmed that apoptosis-inducing bile acids are able to modulate lipid membrane fl uidity, suggesting that their physiological activity could be associated with this effect. Different organelles have been anticipated as targets for cytotoxic bile acids, namely, the plasma membrane ( 17 ) and the mitochondria ( 20 ). Our approach to elucidate this issue was to carry out a quantitative evaluation of the impact of physiologically active DCA concentrations on the membrane order of both these organelles.…”