Gallstones continue to be a major concern of affluent populations. Ample evidence suggests a dietary basis for the problem, i.e. highest prevalence in obese persons with a high-calorie, high-fat intake. Further, altered lipoprotein (LP) metabolism appears implicated and an increased triglyceride (TG) and cholesterol synthesis and VLDL secretion are commonly associated with the disease. It appears that disposition of hepatic cholesterol, originating from de novo synthesis vs that from exogenous (chylomicron remnants) or other lipoprotein cholesterol (LDL, HDL) returning to the liver, dictate bile lithogenicity. The latter depends on whether the liver secretes the cholesterol in bile as free biliary cholesterol (BC) or converts it to bile acids (BAs) via 7-Alpha-OHase. Although reports continue to describe these relationships, a cohesive link between diet, LP metabolism, and bile lipid secretion has not been made in a systematic manner in the same model. The hamster has been widely studied as an effective model of cholelithiasis due to the similarity of its bile lipid and BA patterns with human bile. In the proposed studies we will define specific interrelationships between dietary fats (2 saturated, 2 unsaturated) and cholesterol and their interaction on relevant aspects of lipid and LP metabolism on lithogenic bile formation. To this end, a semipurified diet will be developed for Syrian hamsters with dietary cholesterol and estrogen to induce gallstone formation under physiological dietary conditions (i.e., normal growth). Utilizing variations of this diet we will characterize bile lipids, plasma LPs, VLDL secretion rate, relative rates of TG and PL synthesis, and the relative synthesis and incorporation of newly-synthesized vs LP cholesterol into biliary cholesterol and BAs. From these studies we hope to perfect hamster cholelithiasis to generate an ideal animal model for resolution of mechanisms of cholelithiasis as it relates to individual dietary components and their interactions. Specifically, what role do EFAs play in regulating bile lithogenicity and what is the nature of the genetic variant in this process that distinguishes hypo- vs hyperresponder hamsters in their susceptibility to gallstone formation?
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