Bhat N R, Volpe J J
J Neurochem. 1984 May;42(5):1457-63. doi: 10.1111/j.1471-4159.1984.tb02809.x.
The relation of cellular cholesterol content to a biochemical expression of astrocytic differentiation was investigated in cultured C-6 glial cells. The astrocytic marker, glutamine synthetase, was studied. Cellular sterol content was perturbed with compactin, a specific inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase and, thereby, cholesterol biosynthesis. Depletion of cellular sterol resulted in 72 h in a more than twofold increase in glutamine synthetase activity. Production of various degrees of sterol depletion with different concentrations of compactin demonstrated a striking inverse relationship between glutamine synthetase activity and the cellular sterol/phospholipid molar ratio. That the effect of compactin, in fact, is mediated by depletion of sterol was shown further by prevention of the compactin-induced increase in synthetase activity by simultaneous addition of exogenous cholesterol. Moreover, addition of cholesterol alone to the culture medium led to both a decrease in glutamine synthetase activity and an increase in the sterol/phospholipid molar ratio. The possibility that the compactin-induced increase in glutamine synthetase activity is caused by an increase in synthesis of the enzyme was suggested by prevention of the increase by cycloheximide. The data suggest that astrocytic differentiation is stimulated by a decrease in cellular sterol content. When considered with our previous observation that oligodendroglial differentiation is inhibited by such a decrease, the findings suggest that cellular sterol content is a critical determinant of the direction of glial differentiation, i.e., whether along astrocytic or oligodendroglial lines.
在培养的C-6神经胶质细胞中，研究了细胞胆固醇含量与星形胶质细胞分化的生化表现之间的关系。对星形胶质细胞标志物谷氨酰胺合成酶进行了研究。用美伐他汀（一种3-羟基-3-甲基戊二酰辅酶A还原酶的特异性抑制剂，从而抑制胆固醇生物合成）扰乱细胞固醇含量。细胞固醇耗竭72小时后，谷氨酰胺合成酶活性增加了两倍多。用不同浓度的美伐他汀产生不同程度的固醇耗竭，结果表明谷氨酰胺合成酶活性与细胞固醇/磷脂摩尔比之间存在显著的负相关关系。同时添加外源性胆固醇可防止美伐他汀诱导的合成酶活性增加，这进一步表明美伐他汀的作用实际上是由固醇耗竭介导的。此外，向培养基中单独添加胆固醇会导致谷氨酰胺合成酶活性降低以及固醇/磷脂摩尔比增加。放线菌酮可防止谷氨酰胺合成酶活性增加，这表明美伐他汀诱导的谷氨酰胺合成酶活性增加可能是由该酶合成增加所致。数据表明，细胞固醇含量降低会刺激星形胶质细胞分化。结合我们之前的观察结果，即这种降低会抑制少突胶质细胞分化，这些发现表明细胞固醇含量是胶质细胞分化方向的关键决定因素，即沿星形胶质细胞系还是少突胶质细胞系分化。
