Cholesterol cholelithiasis occurs twice as frequently in women as in men. Pregnancy estrogens and contraceptive steroids increase the risk of acquiring cholesterol gallstones. Pregnancy and administration of estrogens and contraceptive steroids increase biliary cholesterol saturation and secretion.
The aim of this proposal is to identify the probable mechanism(s) and source(s) of the excess biliary cholesterol. Biliary lipid and bile acid composition and secretion, hepatic uptake of chylomicrons, cholesterol absorption and synthesis will be studied in pregnant women, young women taking contraceptive steroids and postmenopausal women taking estrogens. Dietary cholesterol intake will be varied to allow measurement of estrogen/pregnancy effects on a recognized regulatory factor in cholesterol homeostasis. Biliary lipid and bile acid composition will be measured in duodenal bile using standard methods. Biliary cholesterol secretion will be measured using the marker perfusion technique. Cholesterol absorption will be measured with the isotope ratio method in postmenopausal women and by the intestinal perfusion method in the other groups. Cholesterol synthesis will be estimated from the incorporation of 14C-acetate into sterols by mononuclear leukocytes. Hepatic chylomicron uptake will be measured by a technique based upon the hepatic removal of plasma retinyl esters. Changes in cholesterol absorption, synthesis and chylomicron uptake will be related to simultaneous changes in biliary lipid composition and secretion. In other studies biliary cholesterol saturation will be measured during acute alteration of the bile acid pool to reproduct the increased cholic acid/chenode-oxycholic acid ratio found in pregnancy and in contraceptive steroid users. In a related experiment, hamster livers from pregnant animals, those treated with ethinyl estradiol and controls will be isolated and perfused with a medium containing 3H20 and chylomicron remnants labeled with retinyl esters and 14C-cholesterol to measure the rates of chylomicron uptake, cholesterol and bile acid synthesis and the secretion of exogenous and newly synthesized cholesterol into the bile as cholesterol and as bile acids. Compartmental modeling will be employed in data analysis. Hepatic concentration of cholesterol and cholesteryl esters will also be measured.
