Dietary Cholesterol and Defects in Cholesterol Synthesis

描述(申请人提供)：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是一种多发性先天性畸形/智力低下综合征。MKD可引起两种不同的症状，即甲磺酸尿症和高免疫球蛋白血症伴周期性发热综合征。精神和身体发育受损是SLOS和MKD的特征。我们假设SLOS受试者长期补充饮食中添加和不添加他汀类药物的CH会提高CH水平，减少CH前体的合成，并允许足够的胆汁酸合成。在MKD中，改变饮食CH的影响尚不清楚。我们假设低CH饮食将有益于MKD，允许HMG Coar的最大上调，因为我们假设MKD是异戊二烯和脂肪酸的紊乱，而不是CH合成。来自HMG Coar的甲戊酸是CH合成所必需的，但也提供细胞功能所必需的异戊二烯类化合物。此外，正常情况下次要的分解代谢途径，甲戊酸分流，将甲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。在SLOS，异戊二烯合成和甲戊酸分流可能由于这两条通路起跳远端的酶阻断而增加，但在MKD由于近端的阻断而减少。计划进行体外研究，以评估CH暴露和他汀类药物对SLOS、MKD和对照细胞中CH合成、甲戊酸、异戊二烯和甲羟戊酸分流产物的影响。类异戊二烯和分流产物也将在一种新的SLOS小鼠模型中进行分析。平行的活体人体研究将着眼于类固醇和胆汁酸的合成、CH吸收、甲戊酸排泄作为HMG Coar活性的指标、SLOS和MKD中必需的脂肪酸和白三烯、异戊二烯和甲羟戊酸分流产物、改变饮食中的CH和他汀类药物(仅限SLOS)。改变膳食CH(和SLOS中的他汀类药物)对血浆24-S·OH-CH的影响将被评估，这是一种衡量脑CH周转的指标。我们将确定SLOS和MKD基因突变是否决定生化和临床表型，以及某些基因类型是否对改变饮食CH的反应不同。长期对新陈代谢/生长、发育、行为、睡眠、进食、听力和视力进行研究，以确定干预措施是否有用。

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.