REGULATION OF BILE ACID SYNTHESIS IN THE LIVER

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The objective of this proposal is to examine the extent to which individual bile acids and selected bile acid analogues affect the synthesis of bile acids and cholesterol and the binding and uptake of lipoprotein cholesterol. Several in vitro models will be used (cultured rat and human hepatocytes and freshly suspended hepatocytes) that permit the effects of single bile acids to be defined under controlled experimental conditions. The experiments described in the first part of the proposal are designed 1) to measure the relative potency of free and conjugated bile acids and bile acid analogues on bile acid synthesis, 2) to examine the relationship between bile acid structure and inhibitory potency, 3) to determine quantitatively the contribution of cholesterol substrate from newly synthesized cholesterol and from plasma lipoprotein cholesterol, and 4) to establish whether bile acids affect their own synthesis by regulating the availability of cholesterol substrate; for example, by interferring with hepatic cholesterol synthesis or by modulating the uptake of lipoprotein cholesterol. The experiments described in the second part of the proposal are based on the view that the major substrate for bile acid synthesis and biliary cholesterol excretion is plasma lipoprotein cholesterol, and that the first step in hepatic uptake of lipoprotein cholesterol is the binding of plasma lipoproteins to specific liver membrane receptors. The experiments will seek to define which plasma lipoprotein fraction in the predominant contributor of cholesterol substrate for bile acid synthesis and to determine whether bile acids play a role in the regulation of receptor-mediated lipoprotein binding and, thus, in cholesterol uptake by the liver.