Dietary Cholesterol and Defects in Cholesterol Synthesis

我们希望研究改变饮食胆固醇（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）。SLOS是一个多 先天性异常/智力迟钝综合征。MKD引起2种不同的综合征，甲羟戊酸 高免疫球蛋白血症D伴周期性发热综合征。身心受损 发展是SLOS和MKD的标志。我们假设，长期补充维生素D 饮食CH伴或不伴他汀类药物的SLOS受试者将升高CH水平，降低CH前体 合成并允许充分胆汁酸合成。在MKD中，改变饮食CH的影响是 不清楚我们假设低CH饮食对MKD有益，允许最大的上调 由于我们假设MKD是类异戊二烯和脂肪酸而不是CH的紊乱， 合成.来自HMG CoAR的甲羟戊酸对于CH合成是必需的，但也提供类异戊二烯 对细胞功能至关重要。此外，一个正常的次要分解代谢途径，甲羟戊酸 分流，将甲羟戊酸从类异戊二烯和CH合成转向亮氨酸氧化途径。 分流在SLOS中可能是保护性的，而在MKD中可能是有害的。类异戊二烯合成和甲羟戊酸 SLOS中的分流可能会增加，这是由于这两种酶起飞远端的酶阻断所致。 通路，但由于近端阻滞，MKD减少。计划进行体外研究， CH暴露的扰动和他汀类药物对CH合成、甲羟戊酸、类异戊二烯和 SLOS、MKD和对照细胞中的甲羟戊酸分流产物。类异戊二烯和分流产品也将 在新的SLOS小鼠模型中进行分析。平行的体内人体研究将着眼于合成 甾醇和胆汁酸，CH吸收，甲羟戊酸排泄作为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CH和他汀类药物（仅SLOS）。改变饮食CH（和他汀类药物在SLOS中的作用） 对血浆24-S OH-CH（脑CH周转的量度）的影响。我们将确定 SLOS和MKD基因突变是否决定生化和临床表型， 某些基因型是否对改变饮食CH有不同的反应。代谢/生长的研究， 发育、行为、睡眠、进食、听觉和视觉都是长期进行的， 确定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.