Dietary Cholesterol and Defects in Cholesterol Synthesis

膳食胆固醇和胆固醇合成缺陷

• 批准号: 6793582
• 负责人: Robert David Steiner
• 金额: $ 42.22万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-08-20 至 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6793582
• 关键词: Smith Lemli Opitz syndrome; antihypercholesterolemic agent; biotransformation; cholanate compound; cholesterol; clinical research; diet therapy; dietary supplements; enzyme mechanism; gastrointestinal nutrient absorption; human subject; inborn lipid /lipoprotein disorder; isoprenoid; mental retardation; mevalonate; nutrition related tag; patient oriented research; phosphotransferases; steroid biosynthesis

DESCRIPTION (provided by applicant): We wish to study the effects of altering dietary cholesterol (CH) on 2 disorders of CH synthesis: mevalonate kinase deficiency (MKD), and Smith-Lemli-Opitz syndrome (SLOS). SLOS is a multiple congenital anomalies/mental retardation syndrome. MKD causes 2 distinct syndromes, mevalonic aciduria and hyperimmunoglobulinemia D with periodic fever syndrome. Impaired mental and physical development are hallmarks of SLOS and MKD. We hypothesize that long-term supplementation of SLOS subjects with dietary CH with and without statins will raise CH levels, decrease CH precursor synthesis and permit adequate bile acid synthesis. In MKD, the effects of altering dietary CH are unclear. We hypothesize that a low CH diet will be beneficial in MKD, allowing maximal upregulation of HMG CoAR since we postulate that MKD is a disorder of isoprenoid and fatty acid rather than CH synthesis. Mevalonate from HMG CoAR is essential for CH synthesis but also provides isoprenoids essential for cellular function. Furthermore, a normally minor catabolic pathway, the mevalonate shunt, diverts mevalonate from isoprenoid and CH synthesis to the leucine oxidation pathway. Shunting may be protective in SLOS and harmful in MKD. Isoprenoid synthesis and mevalonate shunting may be increased in SLOS due to the enzymatic block distal to the takeoff of these 2 pathways, but decreased in MKD due to the proximal block. In vitro studies are planned to evaluate the effects of perturbations in CH exposure and statins on CH synthesis, mevalonate, isoprenoids, and mevalonate shunt products in SLOS, MKD, and control cells. Isoprenoids and shunt products will also be analyzed in a new SLOS mouse model. Parallel in vivo human studies will look at synthesis of sterols and bile acids, CH absorption, mevalonate excretion as an indicator of HMG CoAR activity, essential fatty acids and leukotrienes, isoprenoids, and mevalonate shunt products in SLOS and MKD, altering dietary CH and statins (SLOS only). The effects of altering dietary CH (and statins in SLOS) on plasma 24-S OH-CH, a measure of brain CH turnover, will be evaluated. We will determine whether mutations in SLOS and MKD genes determine biochemical and clinical phenotype and whether certain genotypes respond differently to altering dietary CH. Studies of metabolism/growth, development, behavior, sleep, feeding, hearing, and vision are performed over the long term to determine if the interventions might be helpful.

描述（由申请人提供）：我们希望研究改变饮食胆固醇（CH）对2种CH合成疾病的影响：Mevalonate激酶缺乏症（MKD）和Smith-Lemli-Opitz综合征（SLOS）。 SLO是多个先天性异常/精神降低综合症。 MKD引起2种不同的综合症，甲瓦硅酸酸尿和高抗蛋白血症D，并带有周期性发烧综合征。精神和身体发展受损是SLOS和MKD的标志。我们假设用和汀类药物对饮食CH的长期补充受试者的长期补充将提高CH水平，降低CH前体的合成并允许足够的胆汁酸合成。在MKD中，改变饮食的效果尚不清楚。我们假设低CH饮食对MKD有益，从而允许HMG Coar的最大上调，因为我们假设MKD是类异型和脂肪酸的疾病，而不是CH合成。 HMG Coar的甲氯酸盐对于CH合成至关重要，但也为细胞功能提供了必不可少的类异胞素。此外，通常是较小的分解代谢途径，甲谷酸酯分流器将大甲酸酯从类异丙酸酯和CH合成转移到亮氨酸氧化途径。分类可能具有SLO的保护性，并且在MKD中有害。由于近端阻滞导致的酶促块，因此，由于近端途径的起飞远端，因此，SLO中的异丙也可以增加SLO的合成和大甲酸盐分流。计划进行体外研究，以评估CH暴露和他汀类药物对CH合成，甲瓦甲酸酯，类异丙酸酯和甲氟甲酸酯对SLOS，MKD和对照细胞中的扰动的影响。类异型和分流产品也将在新的SLOS小鼠模型中进行分析。平行于体内人类研究将考虑固醇和胆汁酸的合成，CH吸收，甲瓦龙蛋白排泄，作为HMG Coar活性，必需脂肪酸和白细胞酸酯，异荷酸酯，异丙酸酯，以及SLOS和MKD中的大甲酸分支机构，仅在饮食中更改饮食中的饮食CH和Stlos（Slos）（SLOS）。将评估改变饮食CH（SLO中的他汀类药物）对血浆24-S OH-CH的影响（脑CH周转量）。我们将确定SLOS和MKD基因中的突变是否确定生化和临床表型，以及某些基因型对改变饮食CH的反应是否有所不同。长期进行新陈代谢/生长，发育，行为，睡眠，喂养，听力和视力的研究，以确定干预措施是否有帮助。