METABOLISM OF COMPLEX LIPIDS OF NERVOUS TISSUES

神经组织复合脂质的代谢

• 批准号: 3846142
• 负责人: P G PENTCHEV
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3846142
• 关键词: HMG coA reductases; Niemann Pick disease; cholesterol; diagnosis design /evaluation; disease /disorder model; enzyme activity; heterozygote; human tissue; inborn metabolism disorder diagnosis; intracellular transport; laboratory mouse; lipid metabolism; low density lipoprotein; molecular pathology; prenatal diagnosis; progesterone; receptor; sphingosine; tissue /cell culture

The metabolic defect in patients with Types C and D Niemann-Pick disease has been shown to be due to abnormal intracellular cholesterol homeostasis. The molecular lesion in these disorders results in: (1) failure to down-regulate LDL receptors on cell membranes; (2) lack of down-regulation of HMGCoA reductase, a key enzyme in cholesterol biosynthesis; and (3) inability to up-regulate acyl cholesterol acyl CoA transferase, the enzyme that catalyzes the esterification of intracellular cholesterol. Tests have been developed and introduced into medical practice for the diagnosis of Types C and D Niemann-Pick disease and the identification of heterozygotes, and the prenatal diagnosis of these conditions. We have observed that the addition of progesterone to cultured skin fibroblasts derived from normal individuals reversibly blocks the intracellular translocation of cholesterol that is similar to that in cells from patients with Type C Niemann-Pick disease (NPC). We also found that naturally occurring organic amines such as stearylamine and sphingosine elicit effects that closely mimic the abnormal cell biology of NPC. Moreover, we discovered that the quantity of sphinganine, a precursor of sphingosine, is greatly increased in the liver of the murine analogue of human NPC. These findings provide considerable additional insight into the pathogenesis of this neurometabolic disorder.

C型和D型尼曼-皮克病患者的代谢缺陷 已被证明是由于细胞内胆固醇异常所致 体内平衡。 这些疾病中的分子损伤导致：(1) 未能下调细胞膜上的 LDL 受体； (2)缺乏 HMGCoA 还原酶（胆固醇中的关键酶）的下调 生物合成； (3) 无法上调酰基胆固醇酰基 CoA 转移酶，催化酯化反应的酶 细胞内胆固醇。 测试已开发并引入 C 型和 D 型尼曼-皮克病诊断的医疗实践 杂合子的鉴定和产前诊断 这些条件。 我们观察到，在培养皮肤中添加黄体酮 来自正常个体的成纤维细胞可逆地阻断 胆固醇在细胞内的易位类似于 来自 C 型尼曼-皮克病 (NPC) 患者的细胞。 我们也 发现天然存在的有机胺，例如硬脂胺和 鞘氨醇引起的效应与异常细胞生物学非常相似 NPC 的。 此外，我们发现二氢鞘氨醇的含量 鞘氨醇的前体，在小鼠肝脏中大大增加 人类 NPC 的类似物。 这些发现提供了相当多的额外信息 深入了解这种神经代谢紊乱的发病机制。