BILE ACID METABOLISM AND HYPERTRIGLYCERIDEMIA

高脂血症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。的交互 胆汁酸和血浆极低密度脂蛋白（VLDL）之间的关系 甘油三酸酯已被认识多年。的中心假设 这些研究表明，胆汁酸通过肝脏的流量， 肝肠循环影响VLDL甘油三酯的产生。的 拟议研究的总体目标是检验假设， 负责肠道胆汁酸吸收的基因的遗传缺陷 可以引起FHTG，并检查胆汁酸可以 调节肝脏VLDL甘油三酯的产生。获得的信息 这些研究将增加我们对 高脂血症的机制，并协助设计新的治疗方法 这个重要的健康问题。以下问题将是 地址： 1.是回肠Na+/胆汁酸共代谢的遗传性功能失调突变， 家族性高脂血症的一个亚型的转运蛋白？一 FHTG的候选基因是回肠Na+/胆汁酸共转运蛋白（ISBT） 负责胆汁酸的肠道回收。ISBT 基因已被克隆，最近发现了一个功能失调的突变 在FHTG患者中。为了回答这个问题，ISBT协会 用连锁分析方法对FHTG家系进行基因和HTG的检测， 将在有胆汁酸的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直接刺激 VLDL生产？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，肝脏分泌的VLDL 将在分离的受试者中测量载脂蛋白B-100（apo B）和甘油三酯。 从喂食对照品的非洲绿色猴获得的灌注肝脏或 含考来烯胺的饮食。 3.胆汁酸影响肝脏VLDL的分子机制是什么 甘油三酸酯的生产？胆汁酸与极低密度脂蛋白的相互作用 将在非洲绿色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 将使用脉冲追踪方案测定甘油三酯和载脂蛋白B， 确定调节步骤。

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).