Lith genes induce overexpression of sterol carrier protein 2(SCP2)during cholesterol (CHOL) gallstone formation

Hypersecretion of Chol into bile is a key defect in gall- stone pathogenesis. Phosphatidylcholine (PC)transfer protein (PCTP) and SCP2 appear to transport PC and Chol in the liver cell, respectively. To explore their role in gallstone for- mation, we correlated mRNA levels with Chol and PC secretion rates in gallstone susceptible C57L and -resistant AKR mice. Male mice were fed a lithogenic diet (15% ht,1% Chol,0,5% cholic acid)for up to 4 weeks. At 7 day intervals, biles and livers were harvested. SCP2 and PCTP mRNA and protein level were quantified with Northern and Western blot analysis, respectively. Lipid secretion rates were determined from bile flow and chemical analysis. Polarizing light microscopy con- firmed the formation gallstones in C57L, but not AKR mice (Hepatology,1995;22:289A). During the 28 day period, a rise (p<0.05) in biliary secretion rates (umol/kg/hr) of Chol (12 4-5 to 254-12) and PC (304-10 to 57±21) and in the Chol/PC ra- tio (0.374-0.06 to 0.43+0.1)was observed in C57L mice. This was associated with a 2fold rise (p<0.05)in SCP2 mRNA and protein levels, but no change for PCTP. Despite an increase (p<0.05) for biliary Chol (54-1 to 84-1) and PC (144-3 to 2544)in AKR mice, there was neither a rise in mRNA and protein levels nor in the Ch01/PC ratio. Hypersecretion of Chol but not PC into bile is associated with a rise in SCP2 gene expression. Because SCP2 and Lith genes are on different chromosomes, Lith genes may code for proteins that regulate SCP2. These data may link Chol hypersecretion to a genetic defect in Chol gallstone formation.