BILE ACID METABOLISM AND HYPERTRIGLYCERIDEMIA

高甘油三酯血症(HTG)是一种常见的脂蛋白代谢紊乱 也是冠心病的潜在危险因素。一种互动 胆汁酸与血浆极低密度脂蛋白之间的关系 甘油三酯已经被认识到很多年了。的中心假说 这些研究表明，胆汁酸在肝脏中的流量 肠-肝循环影响极低密度脂蛋白甘油三酯的产生。这个 这项拟议研究的总体目标是检验以下假设 肠道胆汁酸吸收相关基因的遗传缺陷 可以引起FHTG，并研究胆汁酸可以 调节肝脏极低密度脂蛋白甘油三酯的生成。获取的信息来自 这些研究将增加我们对潜在的 高甘油三酯血症的机制(S)并协助设计新的治疗方法 这一重要的健康问题。以下问题将是 地址： 1.回肠Na+/胆汁酸协同功能异常是否存在遗传性突变 导致家族性高甘油三酯血症的转运蛋白？一个 FHTG的候选基因是回肠Na+/胆汁酸共转运蛋白(ISBT) 它负责胆汁酸的肠道回收。ISBT 基因已经被克隆，最近发现了一种功能失调的突变 在一名FHTG患者身上。为了回答这个问题，ISBT协会 基因和HTG将通过连锁分析来检测DIN FHTG家族和 患有胆汁酸的FHTG患者将筛查ISBT基因突变 吸收不良。 2.通过肝脏的胆汁酸流量减少是否直接刺激 极低密度脂蛋白的产生？对接受胆碱胺治疗的患者的研究表明 胆汁酸回流到肝脏的减少刺激极低密度脂蛋白的产生 甘油三酯。为了直接验证这一假设，肝脏分泌的极低密度脂蛋白 载脂蛋白B-100(Apo B)和甘油三酯将在分离的 灌流的肝脏来自非洲绿猴，喂养对照组或 含胆碱胺的饮食。 胆汁酸影响肝脏极低密度脂蛋白的分子机制是什么 甘油三酯生产？胆汁辅助剂与极低密度脂蛋白的相互作用 将在非洲绿猴的原代培养中研究生产 肝细胞。胆汁酸对极低密度脂蛋白合成和分泌的影响 甘油三酯和载脂蛋白B将使用脉冲追踪法进行测定 确定调控步骤(S)。

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).