Bogdanovic Elena, Sadri Ali-Reza, Catapano Michael, Vance Jean E, Jeschke Marc G
Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, 2075 Bayview Ave, D704, Toronto, ON, Canada M4N 3M5.
Group on the Molecular and Cell Biology of Lipids, Department of Medicine, University of Alberta, 332 HMRC, Edmonton, AB, Canada T6G 2S2.
Neurosci Lett. 2014 Oct 17;582:87-92. doi: 10.1016/j.neulet.2014.09.015. Epub 2014 Sep 16.
Isocitrate dehydrogenase 1 (IDH1) is an evolutionarily conserved enzyme that catalyzes the interconversion of isocitrate to α-ketoglutarate with the concomitant reduction of NADP(+) to NADPH. IDH1 has previously been shown to participate in lipid biosynthesis in various tissues such as the liver and adipose tissue. We examined the potential role of IDH1 in phospholipid metabolism in the brain. Here we show that IDH1 is highly expressed in the brain and astrocytes during embryonic development and the postnatal period and subsequently declines in adulthood. Silencing of IDH1 expression using siRNA in astrocytes isolated from E18.5 mouse cortices led to increased incorporation of [(3)H]-palmitate into the phosphatidylcholines (PCs) and decreased the incorporation of [(3)H]-palmitate into sphingomyelin and the phosphatidylethanolamines (PEs). In pulse-chase experiments, knock-down of IDH1 expression impaired the turnover of PCs and decreased the synthesis of PEs. The decrease in [(3)H]-palmitate incorporation into PEs when IDH1 was knocked-down in astrocytes was not due to impairments within the CDP-ethanolamine pathway or in the rate of decarboxylation of phosphatidylserine (PS). In conclusion, our results reveal a role for IDH1 in the synthesis/turnover of phospholipids in developing astrocytes and highlight the lipid alterations resulting from the loss of wild-type IDH1 activity.
异柠檬酸脱氢酶1（IDH1）是一种进化上保守的酶，它催化异柠檬酸与α-酮戊二酸之间相互转化，同时将NADP(+)还原为NADPH。此前已有研究表明，IDH1参与肝脏和脂肪组织等多种组织中的脂质生物合成。我们研究了IDH1在大脑磷脂代谢中的潜在作用。在此我们表明，IDH1在胚胎发育和出生后大脑及星形胶质细胞中高表达，随后在成年期下降。使用从E18.5小鼠皮质分离的星形胶质细胞中的siRNA沉默IDH1表达，导致[(3)H]-棕榈酸掺入磷脂酰胆碱（PC）增加，而[(3)H]-棕榈酸掺入鞘磷脂和磷脂酰乙醇胺（PE）减少。在脉冲追踪实验中，敲低IDH1表达会损害PC的周转并减少PE的合成。当在星形胶质细胞中敲低IDH1时，[(3)H]-棕榈酸掺入PE减少并非由于CDP-乙醇胺途径内的损伤或磷脂酰丝氨酸（PS）脱羧速率的损伤。总之，我们的结果揭示了IDH1在发育中的星形胶质细胞磷脂合成/周转中的作用，并突出了野生型IDH1活性丧失导致的脂质改变。
