BILE ACID METABOLISM AND HYPERTRIGLYCERIDEMIA

胆汁酸代谢和高甘油三酯血症

• 批准号: 6110213
• 负责人: PAUL A DAWSON
• 金额: $ 19.92万
• 依托单位: WAKE FOREST UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-07-01 至 2000-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6110213
• 关键词: Cercopithecidae; apolipoprotein B; blood lipoprotein metabolism; cholanate compound; cholestyramine; clinical research; dietary lipid; familial hyperlipoproteinemia; family genetics; gastrointestinal absorption /transport; human subject; hypertriglyceridemia; isolation perfusion; liver metabolism; membrane transport proteins; nutrition related tag; tissue /cell culture; triglycerides; very low density lipoprotein

Hypertriglyceridemia (HTG) is a common disorder of lipoprotein metabolism and a potential risk factor for coronary heart disease. An interaction between bile acids and plasma very low density lipoprotein (VLDL) triglyceride has been recognized for many years. The central hypothesis of these studies is that bile acid flux through the liver in the enterohepatic circulation influences VLDL triglyceride production. The overall goals of the proposed research are to test the hypothesis that inherited defects in genes responsible for intestinal bile acid absorption can cause FHTG, and to examine the mechanism by which bile acids can regulate hepatic VLDL triglyceride production. Information obtained from these studies will increase our understanding of the underlying mechanism(s) of hypertriglyceridemia and assist in designing new therapies for this important health problem. The following questions will be addressed: 1. Are inherited dysfunctional mutations in the ileal Na+/bile acid co- transporter responsible for a subset of Familial Hypertriglyceridemia? A candidate gene for FHTG is the ileal Na+/bile acid co-transporter (ISBT) that is responsible for intestinal reclamation of bile acids. The ISBT gene has been cloned and a dysfunctional mutation was recently identified in a FHTG patient. To answer this question, the association of the ISBT gene and HTG will be examine din FHTG families by linkage analysis and the ISBT gene will be screened for mutations in FHTG subjects with bile acid malabsorption. 2. Does a decreased bile acid flux through the liver directly stimulate VLDL production? Studies in cholestyramine-treated patients suggest that a decreased return of bile acids to the liver stimulate production of VLDL triglyceride. To directly test this hypothesis, hepatic secretion of VLDL apolipoprotein B-100 (apo B) and triglyceride will be measured in isolated perfused livers obtained from African green monkeys fed control or cholestyramine-containing diets. 3. What is the molecular mechanism by which bile acid affect hepatic VLDL triglyceride production? The interaction between bile aids and VLDL production will be studied in primary culture of African green monkey hepatocytes. Bile acid effects on the synthesis and secretion of VLDL triglyceride and apo B will be determined using pulse-chase protocols to determine the regulated step(s).

高甘油三酯血症（HTG）是一种常见的脂蛋白代谢紊乱 以及冠心病的潜在危险因素。一次互动 胆汁酸和血浆极低密度脂蛋白 (VLDL) 之间的关系 甘油三酯已被认可多年。中心假设为 这些研究表明胆汁酸通过肝脏 肠肝循环影响极低密度脂蛋白甘油三酯的产生。这 拟议研究的总体目标是检验以下假设： 负责肠道胆汁酸吸收的基因的遗传缺陷 可能会引起 FHTG，并检查胆汁酸可以引起 FHTG 的机制 调节肝脏 VLDL 甘油三酯的产生。获得的信息来自 这些研究将增加我们对底层的理解 高甘油三酯血症的机制并协助设计新疗法 对于这个重要的健康问题。将提出以下问题 解决： 1. 回肠Na+/胆汁酸共存是否存在遗传性功能障碍突变？ 转运蛋白负责家族性高甘油三酯血症的一部分？一个 FHTG 的候选基因是回肠 Na+/胆汁酸协同转运蛋白 (ISBT) 它负责肠道回收胆汁酸。国际广播电视协会 基因已被克隆，最近发现了功能失调的突变 在 FHTG 患者中。为了回答这个问题，ISBT协会 基因和HTG将通过连锁分析在FHTG家族中进行检查， 将在患有胆汁酸的 FHTG 受试者中筛查 ISBT 基因突变 吸收不良。 2. 通过肝脏的胆汁酸流量减少是否会直接刺激 极低密度脂蛋白的产生？对考来烯胺治疗患者的研究表明 胆汁酸返回肝脏的减少刺激 VLDL 的产生 甘油三酯。为了直接检验这一假设，肝脏分泌 VLDL 载脂蛋白 B-100 (apo B) 和甘油三酯将在分离的 从非洲绿猴获得的灌注肝脏，饲喂对照或 含有考来烯胺的饮食。 3. 胆汁酸影响肝脏VLDL的分子机制是什么 甘油三酯的产生？胆汁辅助剂和 VLDL 之间的相互作用 将在非洲绿猴的原代培养中研究生产 肝细胞。胆汁酸对 VLDL 合成和分泌的影响 甘油三酯和载脂蛋白 B 将使用脉冲追踪方案测定 确定规定的步骤。