Biliary cholesterol hypersecretion in gallstone-susceptible mice is associated with hepatic up-regulation of the high-density lipoprotein receptor SRBI

Enhanced hepatocellular trafficking of cholesterol to the bile canaliculus and cholesterol hypersecretion appears critical for gallstone formation. Th erefore, we studied in more detail the hepatic cholesterol transport pathwa ys in a mouse model of cholesterol gallstone disease. Biliary lipid secreti on rates, plasma lipoprotein levels, hepatic expression of lipoprotein rece ptors, lipid regulatory enzymes, and putative cholesterol transporting prot eins were analyzed in gallstone-susceptible C57L/J and gallstone-resistant AKR/J mice, which were fed a lithogenic diet. Biliary cholesterol hypersecr etion in C57L mice was associated with decreased plasma high-density lipopr otein (HDL) cholesterol levels and significant hepatic induction of the HDL receptor (SRBI) and cholesteryl ester hydrolase, In response to the lithog enic diet, fatty-acid binding protein of liver (FABPL) was markedly induced in both mouse strains. Caveolin 1 was elevated only in plasma membranes of gallstone-susceptible C57L mice, which also failed to down-regulate choles terol synthesis. These data suggest a role of the reverse cholesterol trans port pathway for genetically determined gallstone susceptibility in the mou se.