Dietary Cholesterol and Defects in Cholesterol Synthesis

我们希望研究改变膳食胆固醇(CH)对两种CH合成障碍的影响： 甲氧戊酸激酶缺乏症(MKD)和Smith-Lemli-Opitz综合征(SLOS)。SLOS是多个 先天畸形/智力低下综合征。MKD导致两种不同的综合征，甲瓦隆 伴有周期性发热综合征的酸尿症和高免疫球蛋白血症。精神和身体受损 发展是SLOS和MKD的标志。我们假设长期补充 饮食中加和不加他汀类药物的SLOS受试者将升高CH水平，降低CH前体 合成胆汁酸并允许合成足够的胆汁酸。在MKD中，改变饮食中的CH的影响是 不清楚。我们假设低胆固醇饮食对MKD是有益的，允许最大限度的上调 因为我们假设MKD是一种异戊二烯和脂肪酸的紊乱，而不是CH 综合。来自HMG Coar的甲戊酸是合成CH所必需的，但也提供异戊二烯 对细胞功能来说是必不可少的。此外，一种正常的次要分解代谢途径，甲氧戊酸 分流，将甲氧戊酸从类异戊二烯和CH的合成转移到亮氨酸氧化途径。 分流可能在SLOS中起保护作用，在MKD中起有害作用。类异戊二烯的合成与甲氧戊酸 SLOS的分流可能由于这2个基因的起跳远端的酶阻断而增加 径路，但在MKD由于近端传导阻滞而减少。体外研究计划用来评估 CH暴露中的扰动和他汀类药物对CH合成、甲氧戊酸、异戊二烯和 SLOS、MKD和对照细胞中的甲氧戊酸分流产物。类异戊二烯和分流产品也将 在一种新的SLOS小鼠模型中进行分析。平行的活体人体研究将着眼于合成 甾醇和胆汁酸，CH吸收，甲氧戊酸排泄作为HMG Coar活性的指标， SLOS和MKD中的必需脂肪酸和白三烯、类异戊二烯和甲羟戊酸分流产物， 改变饮食中的胆固醇和他汀类药物(仅限SLOS)。改变膳食CH(和他汀类药物)对SLOS的影响 在血浆24-S·OH-CH上，一个衡量脑CH周转的指标将被评估。我们将决定 SLOS和MKD基因突变是否决定生化和临床表型以及 某些基因对改变膳食CH是否有不同的反应。新陈代谢/生长研究， 发育、行为、睡眠、进食、听力和视觉是长期进行的 确定这些干预措施是否有帮助。

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.