REGULATION OF HEPATIC CHOLESTERYL ESTER METABOLISM

肝脏胆固醇酯代谢的调节

• 批准号: 3345102
• 负责人: SIMEON MARGOLIS
• 金额: $ 15.39万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1985
• 资助国家: 美国
• 起止时间: 1985-09-01 至 1988-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3345102
• 关键词: acetyl coA acetyltransferase; catecholamines; cholesterol; cholesterol esters; cyclic AMP; glucagon; hormone regulation /control mechanism; hydroxycholesterols; liver metabolism; mevalonate; phosphorylation; steroid biosynthesis; steroid metabolism; sterol esterase; vasopressins

Hepatic free cholesterol is secreted directly into the bile, is used to form bile acids, is required for lipoprotein production, and regulates the synthesis of cholesterol and receptors for LDL uptake. Cholesteryl ester formation, by acyl CoA: cholesterol acyl transferase (ACAT) and break down by cholesterol ester hydrolase (CEH) is one mechanism to control the cellular content of free cholesterol. Recent studies suggest that covalent phosphorylation regulates the activities of ACAT and the rate-limiting enzymes for cholesterol and bile acid synthesis in the liver and CEH activity in peripheral tissues. The long term objective of these studies is to understand the role of rapid regulation of these enzymes in the overall economy of liver cholesterol. This project is specifically directed toward studies on the effects of phosphorylation on ACAT and CEH. One specific aim is to obtain direct evidence that phosphorylation activates ACAT. These studies involve purifying ACAT, incorporating 32P into ACAT with protein kinases, and demonstrating that cyclic changes in its phosphate content, produced by alternative treatment with phosphatase and protein kinase, correlate with ACAT activity. A second aim is to determine whether hepatic CEH is also controlled by phosphorylation. In this regard, studies similar to those described for ACAT will be carried out with CEH. A third aim is to identify factors that affect cholesteryl ester synthesis and hydrolysis in freshly isolated hepatocytes and to correlate such changes with the activities and phosphorylation states of ACAT and CEH. Initial studies will utilize dibutyryl cAMP. Other agents will include hormones that stimulate protein kinase activity, such as glucagon, vasopressin, and catecholamines, 25-hydroxycholesterol, and mevalonate. The final aim is to examine the effects of in vivo manipulations, such as cholesterol and cholestyramine feeding and mevalonate administration, on the activities and phosphorylation states of ACAT and CEH. These studies have implications for our understanding of atherosclerosis. The balance between cholesterol and its esters may influence cholesterol excretion and hepatic synthesis and uptake of lipoproteins, thereby affecting plasma lipoprotein concentrations. Better knowledge of the regulation of ACAT and CEH in the liver may provide insights into their control in peripheral tissues where cholesteryl ester hydrolysis is required for cholesterol removal by high density lipoproteins.

肝脏的游离胆固醇被直接分泌到胆汁中，用于 形成胆汁酸，是产生脂蛋白所必需的，并调节 胆固醇和低密度脂蛋白摄取受体的合成。胆固醇酯 由酰基辅酶A：胆固醇酰基转移酶(ACAT)形成和分解 通过胆固醇酯水解酶(CEH)控制的机制之一。 游离胆固醇的细胞含量。最近的研究表明，共价 磷酸化调节ACAT的活性和限速 肝脏和CEH中胆固醇和胆汁酸合成的酶 外周组织中的活性。这些研究的长期目标是 就是了解这些酶的快速调节在 肝脏胆固醇的整体经济性。这个项目是专门的 旨在研究磷酸化对ACAT和CEH的影响。 一个特别的目的是获得直接证据，证明磷酸化 激活ACAT。这些研究涉及纯化ACAT，掺入32P 转化为带有蛋白激酶的ACAT，并证明了 它的磷酸盐含量，由磷酸酶替代处理产生 和蛋白激酶，与ACAT活性相关。第二个目标是 确定肝脏CEH是否也受磷酸化控制。在……里面 在这方面，将进行与ACAT描述的研究类似的研究 和CEH一起出去。第三个目标是确定影响胆固醇的因素。 新鲜分离的肝细胞的酯合成和水解性 将这种变化与酶的活性和磷酸化状态联系起来 ACAT和CEH。初步研究将利用二丁酰cAMP。其他代理 将包括刺激蛋白激酶活性的激素，如 胰高血糖素、加压素、儿茶酚胺、25-羟基胆固醇和 甲氧戊酸。最终目的是检查体内的影响。 操作，如胆固醇和胆碱胺喂养和 甲氧戊酸对酶活性和磷酸化状态的影响 ACAT和CEH。 这些研究对我们理解动脉粥样硬化有重要意义。 胆固醇及其酯之间的平衡可能会影响胆固醇。 排泄和肝脏合成和摄取脂蛋白，从而 影响血浆脂蛋白浓度。更好地了解 对肝脏中ACAT和CEH的调节可能会为了解它们的 胆固醇酯水解处周围组织的控制 高密度脂蛋白清除胆固醇所必需的。