Cholesterol gallstones are a serious and expensive complication of the Western diet, commonly occurring in overweight women consuming too many calories and expressing a high plasma lipid, hyperinsulinemic profile. An elevated HDL2 pool seems conducive to gallstone induction for reasons that are unclear. The hamster also develops which the same metabolic profile, including an exaggerated HDL2 level. Thus, chronic feeding (postprandial condition) seems critical to biliary cholesterol saturation. Accordingly this research will investigate the nutritional aspects of this phenomenon by investigating diet-induced modulations in hamster biliary secretion.
The specific aims will be to identify the normal circadian flux (fed/fast cycle) of newly synthesized vs. performed cholesterol into biliary lipids in the hamster fed purified diets; to determine how this flux is altered by specific dietary components manipulated to enhance gallstone formation; and to examine specific lipoproteins contribution to that sterol flux in hamsters and compare these results to similar data to be generated in the human hepatoma cell line (HEP G2 cells) as a potential model for investigating mechanisms of lithogenesis. Methods will include mass measure of cholesterol synthesis with 3H2O, assay of biliary lipids collected by bile fistulas, in addition to the lithogenic index, and gallstones in gallbladder bile and in nascent biliary secretions. An index of hepatic cholesterol metabolism will be based on mRNA abundance for key apoliproteins, AI, E, B and LDL receptor. Collectively these data will provide new insights on the mechanisms of diet-induced gallstone formation.
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