Dietary Cholesterol and Defects in Cholesterol Synthesis

描述（由申请人提供）：我们希望研究改变膳食胆固醇（CH）对2种CH合成障碍的影响：甲羟戊酸激酶缺乏症（MKD）和Smith-Lemli-Opitz综合征（SLOS）。sls是一种多发性先天性异常/智力低下综合征。MKD引起两种不同的综合征，甲羟戊酸尿症和高免疫球蛋白D伴周期性发热综合征。智力和身体发育受损是SLOS和MKD的标志。我们假设长期补充sls受试者的饮食中有或没有他汀类药物的CH会提高CH水平，减少CH前体合成并允许足够的胆汁酸合成。在MKD中，改变饮食中CH的影响尚不清楚。我们假设低CH饮食对MKD有益，允许最大限度地上调HMG CoAR，因为我们假设MKD是类异戊二烯和脂肪酸紊乱，而不是CH合成紊乱。从HMG CoAR中提取的甲羟戊酸盐是CH合成所必需的，但也提供细胞功能所必需的类异戊二烯。此外，一个通常较小的分解代谢途径，甲羟戊酸分流，将甲羟戊酸从类异戊二烯和CH合成转移到亮氨酸氧化途径。分流可能对SLOS有保护作用，对MKD有危害。类异戊二烯合成和甲羟戊酸分流可能在sls中增加，这是由于这两条通路远端的酶阻滞，而在MKD中由于近端的酶阻滞而减少。体外研究计划评估CH暴露和他汀类药物对sls、MKD和对照细胞中CH合成、甲羟戊酸、类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新的sls小鼠模型中进行分析。平行的体内人体研究将着眼于固醇和胆汁酸的合成、CH的吸收、作为HMG CoAR活性指标的甲羟戊酸排泄、必需脂肪酸和白三烯、类异戊二烯和甲羟戊酸分流产物在SLOS和MKD中，改变饮食中的CH和他汀类药物（仅限SLOS）。改变饮食中的总氯甲烷（以及sls中的他汀类药物）对血浆24-S OH-CH（一种衡量脑总氯甲烷转换的指标）的影响将被评估。我们将确定sls和MKD基因的突变是否决定生化和临床表型，以及某些基因型是否对改变饮食中的CH有不同的反应。对代谢/生长、发育、行为、睡眠、喂养、听力和视力进行长期研究，以确定干预措施是否有帮助。

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.