Abstract
Neuropathy target esterase (NTE), is a membrane protein located in the endoplasmic reticulum (ER). NTE has the activity of phospholipase B and can catalyze the deacylation of phosphatidylcholine (PC) and lysophosphatidylcholine (LPC) to glycerylcholine (GPC). It is phosphorylated and aged by organophosphorus compounds (OPs), that induce delayed neuropathy in humans and sensitive animals. Our previous study has reported that the disruption of ER phospholipid homeostasis caused by the NTE inhibition may contribute to the initiation of the organophosphate-induced delayed neurotoxicity (OPIDN), while it is unknown how the disturbed phospholipid homeostasis initiates OPIDN. It is difficult to change phospholipids in in vivo experiments. Therefore, an in vitro model is urgently needed to explain the role of phospholipid homeostasis disorders in OPIDN. In this study, we altered the expression of NTE in SK-N-SH cells and determined its phospholipid component by using HPLC-MS. Our results showed that the changes of NTE affected the levels of PC, sphingomyelin (SM), phosphatidylethanolamine (PE), phosphatidylserine (PS), lysophosphatidylserine (LPS), phosphatidyl-glycerol (PG), and phosphatidylinositol (PI). Our results were consistent with the in vivo results. Furthermore, our findings indicate that the SK-N-SH cell model is a significantly useful method for the further research on how the changes of phospholipid homeostasis initiate the OPIDN, which is easier than the in vivo experiments in practice.
Highlights
Neuropathy target esterase (NTE), formerly known as neurotoxic esterase [1] is the sixth member of the patatin like phospholipase family, known as PNPLA6 [2]
Generation of different NTE expression cells In order to determine the role of NTE in phospholipid metabolism, we transfected SK-N-SH cells with pCDNA-aNTE and pCDNA-NEST, and screened the cells with either pCDNA-aNTE or pCDNA-NEST
Comparative phospholipid omics To study the effect of the changes of NTE on phospholipid homeostasis, phospholipid omics analysis was performed in SK-N-SH, SH/dsRNA-NTE and SH/HA-NEST. 262 phospholipid species from 11 classes in total were identified, including PC, LPC, PE, sphingomyelin (SM), phosphatidylserine (PS), phosphatidylglycerol (PG), phosphatidylinositol (PI), lysophosphatidylethanolamine (LPE), lysophosphatidylserine (LPS), lysophosphatidylglycerol (LPG) and free fatty acid (FFA)
Summary
Neuropathy target esterase (NTE), formerly known as neurotoxic esterase [1] is the sixth member of the patatin like phospholipase family, known as PNPLA6 [2]. OPIDN requires to inhibit more than 70% of NTE activity. The inhibition and aging of NTE were the necessary events for OPIDN. Its importance is mainly reflected in the following four aspects: first, NTE maintains the integrity and the stability of nerve axons during nerve development and differentiation [4,5,6]; Second, NTE plays an important role in catalyzing the degradation of lecithin and in maintaining the metabolic homeostasis of lecithin [7]. Recent studies found that by inhibiting NTE enzyme activity, TOCP affected phosphatidylcholine (PC), lysophosphatidylcholine (LPC) and glycerol phosphate choline (GPC) and impacted the balance of other phospholipids, such as phosphatidylethanolamine (PE). TOCP disturbed the endoplasmic reticulum phospholipids homeostasis by inhibiting NTE activity [11].
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