Argoff C E, Comly M E, Blanchette-Mackie J, Kruth H S, Pye H T, Goldin E, Kaneski C, Vanier M T, Brady R O, Pentchev P G
Developmental and Metabolic Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892.
Biochim Biophys Acta. 1991 Jun 5;1096(4):319-27. doi: 10.1016/0925-4439(91)90068-k.
A uniquely attenuated disruption of cholesterol homeostasis has been characterized in certain Niemann-Pick, type C (NP-C) fibroblasts. Uptake of LDL-cholesterol by cultured fibroblasts derived from two clinically affected brothers with this variant biochemical phenotype led to less intracellular accumulation of unesterified cholesterol than found in other typical cell lines. This limited cholesterol lipidosis in the variant NP-C cells reflected cholesterol processing errors that differed from the cellular lesions in classical NP-C cells in the following ways: (1) a more limited intracellular distribution of the excessive unesterified cholesterol; (2) shorter and more transient delays in the induction of cholesterol-mediated homeostatic responses; and (3) more efficient intracellular transport of exogenously derived cholesterol to the plasma membrane and the endoplasmic reticulum. Activation of acyl-CoA cholesterol acyltransferase (ACAT) was greater than 100-fold in both control and NP-C fibroblasts when cell cultures were preconditioned with 25-hydroxycholesterol, but the subsequent esterification of exogenous non-lipoprotein [3H]cholesterol remained deficient in all NP-C cells. In the variant NP-C cells conditioned with the oxysterol, this esterification of exogenous [3H]cholesterol was less affected than in classical NP-C cultures. The NP-C mutation affects a broad spectrum of metabolic responses related to the processing of exogenously derived cholesterol. Among this pleiotropic array of deficient responses, retarded intracellular cholesterol transport appears most closely linked to the primary mutation. This conclusion is supported by two current observations: (1) the degree to which sterol transport is affected in mutant cells in turn reflects the extent to which cholesterol-homeostatic responses are compromised; and (2) sterol transport remains deficient despite concurrent normal activation of other cellular responses, such as cholesterol esterification.
在某些尼曼-匹克C型（NP-C）成纤维细胞中，已发现一种独特的胆固醇稳态减弱性破坏。来自两名具有这种变异生化表型的临床受累兄弟的培养成纤维细胞对低密度脂蛋白胆固醇（LDL-胆固醇）的摄取，导致细胞内未酯化胆固醇的积累比其他典型细胞系少。变异NP-C细胞中这种有限的胆固醇脂沉积反映了胆固醇加工错误，其与经典NP-C细胞中的细胞病变在以下方面有所不同：（1）过量未酯化胆固醇在细胞内的分布更有限；（2）胆固醇介导的稳态反应诱导延迟更短且更短暂；（3）外源性胆固醇向质膜和内质网的细胞内转运更有效。当细胞培养物用25-羟胆固醇预处理时，对照和成纤维细胞中酰基辅酶A胆固醇酰基转移酶（ACAT）的激活均大于100倍，但随后外源性非脂蛋白[3H]胆固醇的酯化在所有NP-C细胞中仍然不足。在用氧化甾醇预处理的变异NP-C细胞中，外源性[3H]胆固醇的这种酯化比在经典NP-C培养物中受影响更小。NP-C突变影响与外源性胆固醇加工相关的广泛代谢反应。在这一系列多效性的缺陷反应中，细胞内胆固醇转运延迟似乎与原发性突变联系最为紧密。这一结论得到了目前两项观察结果的支持：（1）突变细胞中甾醇转运受影响的程度反过来反映了胆固醇稳态反应受损的程度；（2）尽管其他细胞反应（如胆固醇酯化）同时正常激活，但甾醇转运仍然不足。
