Changes in cholesterol biosynthetic and transport pathways after excitotoxicity
Changes in cholesterol biosynthetic and transport pathways after excitotoxicity
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DOI：
10.1111/j.1471-4159.2009.06449.x
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发表时间：
2010-01-01
影响因子：
4.7
通讯作者：
Jenner, Andrew M.
中科院分区：
文献类型：
--
作者：
Kim, Ji-Hyun;Jittiwat, Jinatta;Jenner, Andrew M.
本研究旨在阐明红藻氨酸兴奋毒性后大鼠海马区胆固醇生物合成酶和转运蛋白基因表达及活性的变化。海人藻酸损伤后1周，变性的海马区胆固醇水平显著升高，达到正常水平的两倍。海人藻氨酸注射后各时间点大鼠海马匀浆中胆固醇生物合成转录因子SREBP-2和速率控制酶HMG-CoA(3-羟基-3-甲基-戊二酰辅酶A)的mRNA表达均显著降低，羊毛醇合成酶和细胞色素P51的表达在海人藻氨酸注射后1周和2周分别下降。GC-MS分析表明，在海人藻氨酸注射后1天，胆固醇生物合成前体羊毛甾醇、桥粒甾醇和7-脱氢胆固醇显著增加，这可能反映了受损神经元的生物合成，而在海人藻氨酸注射后1周和2周，变性海马区胶质增生时，胆固醇生物合成前体显著减少。在海藻氨酸损伤的海马区，胆固醇自氧化水平升高，包括7个酮类胆固醇和胆固醇环氧化物。此外，在神经元中检测到胆固醇转运蛋白ABCA1的表达缺失，但在海人藻酸损伤后检测到星形胶质细胞的表达增加。结果表明，受损神经元中胆固醇生物合成增加和ABCA1表达缺失可能导致变性海马区胆固醇含量增加。胆固醇的增加可能导致胆固醇氧化产物的形成增加，而胆固醇氧化产物已被证明对神经元有害。
The present study was carried out to elucidate changes in the gene expression and activity of cholesterol biosynthetic enzymes and transporters in the rat hippocampus after kainate excitotoxicity. Significantly increased cholesterol level was detected in the degenerating hippocampus, reaching double normal levels at 1 week after kainate injury. RT-PCR analyses of hippocampal homogenates showed significantly decreased mRNA expression of the transcription factor controlling cholesterol biosynthesis SREBP-2, and the rate-controlling enzyme HMG-CoA (3-hydroxy-3-methyl-glutaryl-CoA) reductase at all time points after kainate injection; and decreased lanosterol synthase and CYP51 at 1 and 2 weeks post-kainate injection respectively. GC-MS analyses showed a significant increase in cholesterol biosynthetic precursors lanosterol, desmosterol and 7-dehydrocholesterol at 1 day after kainate injection presumably reflecting biosysnthesis in injured neurons, and significant decreases in precursors at 1 and 2 weeks post-kainate injection, at time of gliosis in the degenerating hippocampus. Levels of cholesterol autooxidation including 7 ketocholesterol and cholesterol epoxides were elevated in the kainate lesioned hippocampus. Furthermore, loss of expression of the cholesterol transporter, ABCA1 was detected in neurons, but increased expression in astrocytes was detected after kainate lesions. The results suggest that increased cholesterol biosynthesis and loss of ABCA1 expression in injured neurons might result in increase in cholesterol in the degenerating hippocampus. The increased cholesterol might predispose to increased formation of cholesterol oxidation products which have been shown to be toxic to neurons.