Effect of Cholesterol Reduction on Receptor Signaling in Neurons
Effect of Cholesterol Reduction on Receptor Signaling in Neurons
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DOI：
10.1074/jbc.m115.664367
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发表时间：
2015-10-30
影响因子：
4.8
通讯作者：
Kahn, C. Ronald
中科院分区：
文献类型：
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作者：
Fukui, Kenji;Ferris, Heather A.;Kahn, C. Ronald
糖尿病与各种并发症有关，包括中枢神经系统(CNS)的改变。我们最近发现，糖尿病导致大脑中胆固醇合成减少，这是由于胰岛素刺激减少了SREBP2介导的神经元和神经胶质细胞中的胆固醇合成。在本研究中，我们使用三种独立的方法：1)暴露于甲基-β-环糊精，2)用HMG-CoA还原酶抑制剂辛伐他汀治疗，3)shRNA介导的SREBP2下调，探讨了胆固醇降低对体外培养的下丘脑GT1-7细胞神经元功能的影响。这三种方法都使细胞胆固醇含量降低了20%-31%，与糖尿病患者观察到的胆固醇合成减少类似。在胰岛素、胰岛素样生长因子-1或神经营养因子(NGF和BDNF)刺激下，所有去胆固醇的神经元来源的细胞都表现出IRS-1和AKT的磷酸化/活化降低，与降低的方法无关。甲基-β-环糊精和他汀类药物处理后ERK的磷酸化/活化也降低，而SREBP2基因敲除后细胞中ERK的磷酸化/活化增加。此外，在淀粉样β蛋白存在的情况下，细胞的凋亡率增加。细胞胆固醇的降低也导致了基础自噬的增加和葡萄糖剥夺诱导的自噬的损害。综上所述，这些数据表明，与糖尿病脑中观察到的情况类似，神经源性胆固醇含量的降低会导致胰岛素和生长因子抵抗的状态，这可能会导致糖尿病的中枢神经系统相关并发症，包括增加神经退行性疾病的风险，如阿尔茨海默病。
Diabetes mellitus is associated with a variety of complications, including alterations in the central nervous system (CNS). We have recently shown that diabetes results in a reduction of cholesterol synthesis in the brain due to decreased insulin stimulation of SREBP2-mediated cholesterol synthesis in neuronal and glial cells. In the present study, we explored the effects of the decrease in cholesterol on neuronal cell function using GT1-7 hypothalamic cells subjected to cholesterol depletion in vitro using three independent methods: 1) exposure to methyl-beta-cyclodextrin, 2) treatment with the HMG-CoA reductase inhibitor simvastatin, and 3) shRNA-mediated knockdown of SREBP2. All three methods produced 20-31% reductions in cellular cholesterol content, similar to the decrease in cholesterol synthesis observed in diabetes. All cholesterol-depleted neuron-derived cells, independent of the method of reduction, exhibited decreased phosphorylation/activation of IRS-1 and AKT following stimulation by insulin, insulin-like growth factor-1, or the neurotrophins (NGF and BDNF). ERK phosphorylation/activation was also decreased after methyl-beta-cyclodextrin and statin treatment but increased in cells following SREBP2 knockdown. In addition, apoptosis in the presence of amyloid-beta was increased. Reduction in cellular cholesterol also resulted in increased basal autophagy and impairment of induction of autophagy by glucose deprivation. Together, these data indicate that a reduction in neuron-derived cholesterol content, similar to that observed in diabetic brain, creates a state of insulin and growth factor resistance that could contribute to CNS-related complications of diabetes, including increased risk of neurodegenerative diseases, such as Alzheimer disease.