PMID- 24040277 OWN - NLM STAT- MEDLINE DCOM- 20140603 LR - 20211021 IS - 1932-6203 (Electronic) IS - 1932-6203 (Linking) VI - 8 IP - 9 DP - 2013 TI - Simvastatin induced neurite outgrowth unveils role of cell surface cholesterol and acetyl CoA carboxylase in SH-SY5Y cells. PG - e74547 LID - 10.1371/journal.pone.0074547 [doi] LID - e74547 AB - Statins are known to modulate cell surface cholesterol (CSC) and AMP-activated protein kinase (AMPK) in non-neural cells; however no study demonstrates whether CSC and AMPK may regulate simvastatin induced neuritogenesis (SIN). We found that simvastatin (SIM) maintains CSC as shown by Fillipin III staining, Flotillin-2 protein expression / localization and phosphorylation of various receptor tyrosine kinases (RTKs) in the plasma membrane. Modulation of CSC revealed that SIN is critically dependent on this CSC. Simultaneously, phospho array for mitogen activated protein kinases (MAPKs) revealed PI3K / Akt as intracellular pathway which modulates lipid pathway by inhibiting AMPK activation. Though, SIM led to a transient increase in AMPK phosphorylation followed by a sudden decline; the effect was independent of PI3K. Strikingly, AMPK phosphorylation was regulated by protein phosphatase 2A (PP2A) activity which was enhanced upon SIM treatment as evidenced by increase in threonine phosphorylation. Moreover, it was observed that addition of AMP analogue and PP2A inhibitor inhibited SIN. Bio-composition of neurites shows that lipids form a major part of neurites and AMPK is known to regulate lipid metabolism majorly through acetyl CoA carboxylase (ACC). AMPK activity is negative regulator of ACC activity and we found that phosphorylation of ACC started to decrease after 6 hrs which becomes more pronounced at 12 hrs. Addition of ACC inhibitor showed that SIN is dependent on ACC activity. Simultaneously, addition of Fatty acid synthase (FAS) inhibitor confirmed that endogenous lipid pathway is important for SIN. We further investigated SREBP-1 pathway activation which controls ACC and FAS at transcriptional level. However, SIM did not affect SREBP-1 processing and transcription of its target genes likes ACC1 and FAS. In conclusion, this study highlights a distinct role of CSC and ACC in SIN which might have implication in process of neuronal differentiation induced by other agents. FAU - Raina, Varshiesh AU - Raina V AD - Molecular Sciences Laboratory, National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi, Delhi, India. FAU - Gupta, Sarika AU - Gupta S FAU - Yadav, Saurabh AU - Yadav S FAU - Surolia, Avadhesha AU - Surolia A LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20130911 PL - United States TA - PLoS One JT - PloS one JID - 101285081 RN - 0 (Enzyme Inhibitors) RN - 0 (Membrane Proteins) RN - 0 (flotillins) RN - 97C5T2UQ7J (Cholesterol) RN - AGG2FN16EV (Simvastatin) RN - EC 2.3.1.85 (FASN protein, human) RN - EC 2.3.1.85 (Fatty Acid Synthase, Type I) RN - EC 2.7.1.- (Phosphatidylinositol 3-Kinases) RN - EC 2.7.10.1 (Receptor Protein-Tyrosine Kinases) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) RN - EC 2.7.11.31 (AMP-Activated Protein Kinases) RN - EC 3.1.3.16 (Protein Phosphatase 2) RN - EC 6.4.1.2 (Acetyl-CoA Carboxylase) SB - IM MH - AMP-Activated Protein Kinases/genetics/metabolism MH - Acetyl-CoA Carboxylase/antagonists & inhibitors/genetics/*metabolism MH - Cell Line, Tumor MH - Cell Membrane/chemistry/metabolism MH - Cholesterol/*metabolism MH - Enzyme Inhibitors/pharmacology MH - Fatty Acid Synthase, Type I/antagonists & inhibitors/genetics/metabolism MH - *Gene Expression Regulation MH - Humans MH - Lipid Metabolism/drug effects MH - Membrane Proteins/genetics/metabolism MH - Neurites/*metabolism/ultrastructure MH - Phosphatidylinositol 3-Kinases/genetics/metabolism MH - Phosphorylation MH - Protein Phosphatase 2/genetics/metabolism MH - Proto-Oncogene Proteins c-akt/genetics/metabolism MH - Receptor Protein-Tyrosine Kinases/genetics/metabolism MH - Signal Transduction MH - Simvastatin/*pharmacology PMC - PMC3770597 COIS- Competing Interests: Prof. AS, a co-author in this paper, is the member of editorial board. This does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials. EDAT- 2013/09/17 06:00 MHDA- 2014/06/04 06:00 PMCR- 2013/09/11 CRDT- 2013/09/17 06:00 PHST- 2013/06/13 00:00 [received] PHST- 2013/08/02 00:00 [accepted] PHST- 2013/09/17 06:00 [entrez] PHST- 2013/09/17 06:00 [pubmed] PHST- 2014/06/04 06:00 [medline] PHST- 2013/09/11 00:00 [pmc-release] AID - PONE-D-13-24615 [pii] AID - 10.1371/journal.pone.0074547 [doi] PST - epublish SO - PLoS One. 2013 Sep 11;8(9):e74547. doi: 10.1371/journal.pone.0074547. eCollection 2013.