Sitosterolemia

这项资助的主要目的是确定谷固醇血症的分子、生化和临床缺陷。在这种隐性遗传性疾病中，纯合子表现为动脉粥样硬化加速，伴有主动脉狭窄、致命性心肌梗死、肌腱和结节状黄瘤、红细胞变形和血小板减少的溶血性发作，以及致残性关节炎的发作。化学上，植物甾醇(谷甾醇、豆甾醇、菜籽醇和燕麦甾醇)和它们各自的5α-二氢衍生物(谷甾醇和菜籽醇)和胆甾醇在除大脑以外的所有组织中积累，这是因为促进了肠道吸收和减少了肝脏清除。此外，在低密度脂蛋白受体上调的单核细胞中，胆固醇的生物合成被不协调地下调，从而产生更多的胆固醇和植物类固醇沉积，使细胞类似于致动脉粥样硬化的泡沫细胞。主要的研究目标是(1)定位和克隆谷甾醇血症基因，该基因被定位于2p21，序列突变，并通过突变产物允许植物类固醇在肠道细胞中不受限制地摄取和运输来阐明其机制。策略包括用一组密集的微功能标记进行精细定位，将异常基因区域缩小到大约1 cM，构建YAC重叠群和BAC重叠群，从可疑区域和邻近区域构建关键的cDNA。对该区域的候选基因进行测序，以寻找可能的突变。来自30个谷甾醇症家系的40个受影响纯合子的DNA已经组装好。(2)研究与人类谷甾醇血症相似的3种大鼠模型的胆固醇和植物甾醇代谢，其中油菜籽甾醇和谷甾醇约占血浆固醇的15%。在这些模型中，我们建议测量谷甾醇和胆固醇的吸收，评估胆固醇的生物合成(在人类谷甾醇血症中受到抑制)，并评估长期喂饲胆固醇对动脉粥样硬化、植物类固醇和胆固醇积累和代谢的影响。(3)研究谷甾醇(24-乙基胆固醇)转化为胆酸和鹅去氧胆酸的途径。Sitosterolia是一种罕见的疾病，但了解促进类固醇吸收和积累的机制将为在普通人群中制定更好的动脉粥样硬化治疗方案提供关键信息。

The major aims of this grant are to define the molecular, biochemical, and clinical defects in sitosterolemia. In this recessively inherited disease, homozygotes show accelerated atherosclerosis with aortic stenosis, fatal myocardial infarctions, tendon and tuberous xanthomas, hemolytic episodes with deformed erythrocytes and thrombocytopenia, and attacks of disabling arthritis. Chemically, plant sterols (sitosterol, stigmasterol, campesterol, and avenosterol) and their respective 5alpha-dihydro derivatives (sitostanol and campestanol) and cholestanol accumulate in all tissues except brain because of enhanced intestinal absorption and reduced hepatic removal. In addition, cholesterol biosynthesis is discordantly down-regulated in monocytes with upregulated LDL receptors to produce increased cholesterol and plant sterol deposits such that the cells resemble atherogenic foam cells. Key research objectives are (1) locate and clone the sitosterolemia gene responsible for hyperabsorption that has been mapped to 2p21, sequence mutations, and elucidate the mechanism by with the mutated product permits unrestricted uptake and transport of plant sterols through the enterocyte. Strategies include fine mapping with a dense set of microsatilliate markers to narrow the abnormal gene region to approximately 1cM, construction of YAC contig and BAC contig with critical cDNAs from the suspected and adjoining regions. Sequence candidate genes from the region for possible mutations. DNA from 40 affected homozygotes from 30 sitosterolemic families have been assembled. (2) Investigate cholesterol and plant sterol metabolism in 3 rat models where campesterol and sitosterol constitute approximately 15 percent of the plasma sterols similar to human sitosterolemia. In these models, we propose to measure sitosterol and cholesterol absorption, assess cholesterol biosynthesis (inhibited in human sitosterolemia) and evaluate the effect of long term cholesterol feeding on development of atherosclerosis, plant sterol and cholesterol accumulation and metabolism. (3) Examine the conversion of sitosterol (24-ethyl cholesterol) to cholic acid and chenodeoxycholic acid and ascertain the pathway. Sitosterolemia is a rare disease but understanding the mechanism of enhanced sterol absorption and accumulation will provide key information to formulate better treatment of atherosclerosis in the general population.