The bile fluid contains various lipids that are secreted at the canalicular
membrane of hepatocytes. As the secretion mechanism is still a matter of
debate and a direct experimental observation of the secretion process is not
possible so far, we used a mathematical model to simulate the extraction of
the major bile lipids cholesterol, phosphatidylcholine and sphingomyelin from
the outer leaflet of the canalicular membrane. Lipid diffusion was modeled as
random movement on a triangular lattice governed by next-neighbor interaction
energies. Phase separation in liquid-ordered and liquid-disordered domains was
modeled by assigning two alternative ordering states to each lipid species and
minimization of next-neighbor ordering energies. Parameterization of the model
was performed such that experimentally determined diffusion rates and phases
in ternary lipid mixtures of model membranes were correctly recapitulated. The
model describes the spontaneous formation of nanodomains in the external
leaflet of the canalicular membrane in a time window between 0.1 ms to 10 ms
at varying lipid proportions. The extraction of lipid patches from the bile
salt soluble nanodomain into the bile reproduced observed biliary phospholipid
compositions for a physiologi-cal membrane composition. Comparing the outcome
of model simulations with available experi-mental observations clearly favors
the extraction of tiny membrane patches composed of about 100–400 lipids as
the likely mechanism of biliary lipid secretion
