Gap junctions (GJ) are membrane channels made of connexins (Cx) that allow direct communication between adjacent cells. In the liver, GJ are involved in the propagation of signals that regulate important hepatic functions such as glycogenolysis or bile secretion.

Previously, we have shown that cholestatic bile acids (BA) inhibit gap junction permeability (GJP) (1). This inhibition is fast, dose-dependent, reversible and not specific for a type of Cx. Well-known fast blocking mechanisms of GJP such as pH variation or PKC activation were not responsible for this inhibition. GJ are known to be localized in cholesterol rich microdomains of the membrane. We looked for the effect of lipid environment, especially cholesterol membrane content on GJP in rat hepatocyte doublets. GJP was assessed by fluorescent dye transfer, using the Fluorescence Recovery After Photobleaching method. Results show that depletion in membrane cholesterol induces closure of GJ. This effect is reversed by replenishment of membrane with soluble cholesterol. Moreover, enrichment of membrane cholesterol content protects the cells from GJP inhibition induced by cholestatic BA. Although membrane fluidity seems not to be affected by BA under our conditions, our results suggest that these molecules, due to their detergent properties, could inhibit the GJP by modifying the lipid environment of Cx. In conclusion, despite the precise mechanism of action of BA on GJP remains to be determined, our results point out the importance of membrane cholesterol content for the functioning of GJ.

1) Boucherie S. et al., 2005, J Hepatol. 42(2):244-51