Computer Simulations Suggest a Key Role of Membranous Nanodomains in Biliary Lipid Secretion
Figure 5
Illustration of the molecular mechanisms proposed for biliary lipid secretion.
Lipids arrive at the apical membrane of the hepatocyte by various modes of transportation (vesicular, lipid-exchange proteins, lateral membrane transport). Bile salts (BS) are secreted into the canaliculus by the bile-salt export pump (BSEP). Inter-leaflet lipid exchange (indicated by the black double-arrows) by various ABC transporters and P-type ATPases (e.g. MDR1, MDR3, MRP1) establish an asymmetric lipid distribution between the inner and outer hemi-leaflet with CH, PC and SM enriched in the exoplasmic leaflet in a mixture which allows the spontaneous formation of Lo and Ld nanodomains. BS preferentially solubilize lipids of the Ld nanodomains. Mechanisms of lipid extraction currently discussed in the literature envisage (A) extraction of single membrane lipids (mostly PC) by BS micelles under formation of mixed micelles or (B) exo-vesiculation of membrane patches which form mixed micelles. Primary micelles may rapidly fuse to larger lipid vesicles (micelle-to-vesicle transition). The results of our simulation strongly favor the secretion mechanism B (lipid-patch extraction).