REGULATION OF BILE ACID SYNTHESIS IN THE LIVER

这项建议的目标是检查个人在多大程度上 胆汁酸及其类似物影响胆汁的合成 酸和胆固醇与脂蛋白的结合和摄取 胆固醇。将使用几种体外模型(培养的大鼠和人 肝细胞和新鲜悬浮的肝细胞)，这些细胞允许 单一胆汁酸将在受控的实验条件下定义。 建议的第一部分描述的实验是设计的1) 测定游离和结合胆汁酸与胆汁的相对效价 酸性类似物对胆汁酸合成的影响，2)考察两者之间的关系 胆汁酸结构与抑制力之间的关系，3)测定 新发现的胆固醇底物的定量贡献 合成胆固醇和来自血浆脂蛋白胆固醇，以及4)到 确定胆汁酸是否通过调节 胆固醇底物的可用性；例如，通过干扰 肝脏胆固醇合成或通过调节脂蛋白的摄取 胆固醇。 提案第二部分中描述的实验是基于 胆汁酸合成的主要底物与胆汁 胆固醇排泄是血浆脂蛋白胆固醇的第一位 肝脏吸收脂蛋白胆固醇的步骤是与血浆的结合 脂蛋白结合到特定的肝膜受体。这些实验将会 试图确定哪种血浆脂蛋白组分是主要的 胆汁酸合成的胆固醇底物的贡献者 确定胆汁酸是否在调节胆汁酸代谢中起作用 受体介导的脂蛋白结合，从而在胆固醇吸收中通过 肝脏。

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.