Relationship of Apo B and BHMT: Nutrition and Physiology

Apo B 和 BHMT 的关系：营养和生理学

• 批准号: 6795467
• 负责人: JANET DEHOFF SPARKS
• 金额: $ 19.69万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-30 至 2006-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6795467
• 关键词: apolipoprotein B; betaine compound; cell line; diet; gene environment interaction; gene expression; gene targeting; genetically modified animals; homocysteine; immunoprecipitation; laboratory mouse; laboratory rabbit; laboratory rat; liver cells; liver metabolism; messenger RNA; methylation; methyltransferase; nutrition related tag; protein metabolism; protein protein interaction; radioassay; tissue /cell culture; transfection

DESCRIPTION (provided by applicant): Apolipoprotein B (Apo B) is important in lipid transport in lipoproteins (LP), and as a factor associated with risk of macrovascular disease complications (heart attacks, strokes). B48 and B100 are forms of apo B that, in humans, represent intestinal and hepatic products of translation that are derived from edited and unedited apo B mRNA transcribed from a single copy gene. In McArdle RH-7777 (McA) cells, the restoration of betaine homocysteine S-methyltransferase (BHMT) expression through transfection is positively correlated with apo B mRNA abundance and increases in B48 and B100 secretion. BHMT catalyzes transfer of a methyl group from betaine to homocysteine to form methionine. BHMT and methionine synthase contribute equally to methionine formation from homocysteine in rat liver. BHMT can be induced in a variety of nutritional states in vivo. Aim 1 is to establish the physiological relationship between BHMT and apo B. Using dietary conditions that alter BHMT expression, changes in apo B mRNA will be evaluated in rats. Aim 2 will evaluate the impact of apo B mRNA and BHMT pathways on hepatic lipoprotein metabolism in rat hepatocytes (RH) and BHMT-transfected McA cells. Hepatic biogenesis of B100 and B48 will be studied including apo B translation, intracellular LP assembly, apo B degradation, and LP secretion. In order to assess mechanisms of apo B mRNA abundance changes, apo B mRNA stability and apo B gene transcription will be documented. BHMT may function in hepatic lipid metabolism directly, and experiments will test whether BHMT mediates methyl transfer from betaine to phosphatidylethanolamine in the formation of phosphatidyicholme necessary in apo B-Lp secretion. The overall research goal is to understand and characterize BHMT metabolic pathways and potential relationships to apo B biogenesis. A potential link of two pathways whose products or intermediates are associated with increased cardiovascular disease risk could be established.

描述(由申请人提供)：载脂蛋白B(Apo B)在脂蛋白(LP)中的脂质运输中非常重要，也是与大血管疾病并发症(心脏病发作、中风)风险相关的一个因素。B48和B100是载脂蛋白B的形式，在人类中代表肠道和肝脏的翻译产物，这些产物是从单一拷贝基因转录的经过编辑和未经编辑的载脂蛋白B mRNA获得的。 在McArdle RH-7777(MCA)细胞中，通过转基因恢复甜菜碱同型半胱氨酸S甲基转移酶的表达与载脂蛋白B基因丰度、B48和B100分泌增加呈正相关。BHMT催化从甜菜碱到同型半胱氨酸的甲基转移形成蛋氨酸。BHMT和蛋氨酸合酶起作用 与同型半胱氨酸在大鼠肝脏中形成蛋氨酸的作用相同。BHMT在体内可在多种营养状态下被诱导。 目的一是建立BHMT与apo B之间的生理联系，利用改变BHMT表达的饮食条件，观察大鼠apo B基因表达的变化。 目的研究载脂蛋白B(Apo B)m RNA和BHMT途径对大鼠肝细胞(RH)和转BHMT的大脑中动脉(MCA)细胞肝脂蛋白代谢的影响。将研究B100和B48的肝脏生物发生，包括载脂蛋白B的翻译、细胞内脂蛋白的组装、载脂蛋白B的降解和脂蛋白的分泌。为了评估载脂蛋白B基因丰度变化的机制，将记录载脂蛋白B基因转录和载脂蛋白B基因转录的稳定性。BHMT可能直接作用于肝脏的脂质代谢，实验将测试BHMT是否介导甜菜碱到磷脂酰乙醇胺的甲基转移，从而形成载脂蛋白B-LP分泌所需的磷脂酰胆碱。 总体研究目标是了解和表征BHMT的代谢途径和与载脂蛋白B生物发生的潜在关系。其产品或中间体与心血管疾病风险增加相关的两条途径的潜在联系可能被建立。