title: Cholesterol 24S-Hydroxylase Overexpression Inhibits the Liver X Receptor (LXR) Pathway by Activating Small Guanosine Triphosphate-Binding Proteins (sGTPases) in Neuronal Cells.
abstract: The neuronal-specific cholesterol 24S-hydroxylase (CYP46A1) is important for brain cholesterol elimination. Cyp46a1 null mice exhibit severe deficiencies in learning and hippocampal long-term potentiation, suggested to be caused by a decrease in isoprenoid intermediates of the mevalonate pathway. Conversely, transgenic mice overexpressing CYP46A1 show an improved cognitive function. These results raised the question of whether CYP46A1 expression can modulate the activity of proteins that are crucial for neuronal function, namely of isoprenylated small guanosine triphosphate-binding proteins (sGTPases). Our results show that CYP46A1 overexpression in SH-SY5Y neuroblastoma cells and in primary cultures of rat cortical neurons leads to an increase in 3-hydroxy-3-methyl-glutaryl-CoA reductase activity and to an overall increase in membrane levels of RhoA, Rac1, Cdc42 and Rab8. This increase is accompanied by a specific increase in RhoA activation. Interestingly, treatment with lovastatin or a geranylgeranyltransferase-I inhibitor abolished the CYP46A1 effect. The CYP46A1-mediated increase in sGTPases membrane abundance was confirmed in vivo, in membrane fractions obtained from transgenic mice overexpressing this enzyme. Moreover, CYP46A1 overexpression leads to a decrease in the liver X receptor (LXR) transcriptional activity and in the mRNA levels of ATP-binding cassette transporter 1, sub-family A, member 1 and apolipoprotein E. This effect was abolished by inhibition of prenylation or by co-transfection of a RhoA dominant-negative mutant. Our results suggest a novel regulatory axis in neurons; under conditions of membrane cholesterol reduction by increased CYP46A1 expression, neurons increase isoprenoid synthesis and sGTPase prenylation. This leads to a reduction in LXR activity, and consequently to a decrease in the expression of LXR target genes.
authors.affiliation: Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003, Lisbon, Portugal.
authors.forename: Miguel
authors.initials: M
authors.lastname: Moutinho
authors.forename: Maria João
authors.initials: MJ
authors.lastname: Nunes
authors.forename: Anita Q
authors.initials: AQ
authors.lastname: Gomes
authors.forename: Maria João
authors.initials: MJ
authors.lastname: Gama
authors.forename: Angel
authors.initials: A
authors.lastname: Cedazo-Minguez
authors.forename: Cecília M P
authors.initials: CM
authors.lastname: Rodrigues
authors.forename: Ingemar
authors.initials: I
authors.lastname: Björkhem
authors.forename: Elsa
authors.initials: E
authors.lastname: Rodrigues
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism*; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism; D000072556:Cholesterol 24-Hydroxylase; D020558:GTP Phosphohydrolases / Q000378:metabolism; D006801:Humans; D000071518:Liver X Receptors; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism*; D057093:Orphan Nuclear Receptors / Q000378:metabolism*; D013250:Steroid Hydroxylases / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D002784:Cholesterol; D013250:Steroid Hydroxylases; D000072556:Cholesterol 24-Hydroxylase; D020558:GTP Phosphohydrolases
references.citation: J Biol Chem. 2001 Dec 28;276(52):48702-8
references.pmid: 11641412
references.citation: Neuroreport. 1996 Jul 29;7(11):1733-9
references.pmid: 8905654
references.citation: EMBO J. 2001 May 1;20(9):2202-13
references.pmid: 11331586
references.citation: J Biol Chem. 2005 Dec 30;280(52):42759-65
references.pmid: 16267051
references.citation: Brain Pathol. 2012 Mar;22(2):175-87
references.pmid: 21767321
references.citation: J Biol Chem. 2003 Feb 7;278(6):4168-75
references.pmid: 12458210
references.citation: Proc Natl Acad Sci U S A. 1999 Jun 22;96(13):7238-43
references.pmid: 10377398
references.citation: J Neurochem. 2008 Jul;106(2):835-49
references.pmid: 18445135
references.citation: J Neurosci. 2007 Jun 13;27(24):6417-27
references.pmid: 17567802
references.citation: Ther Clin Risk Manag. 2008 Jun;4(3):605-15
references.pmid: 18827856
references.citation: EMBO J. 2012 Apr 4;31(7):1764-73
references.pmid: 22343944
references.citation: J Biol Chem. 1997 Feb 7;272(6):3137-40
references.pmid: 9013544
references.citation: J Lipid Res. 2006 Mar;47(3):467-75
references.pmid: 16401880
references.citation: J Neuropathol Exp Neurol. 1996 Mar;55(3):372-80
references.pmid: 8786396
references.citation: Physiol Rev. 2001 Jan;81(1):153-208
references.pmid: 11152757
references.citation: J Neurooncol. 2012 Jul;108(3):333-9
references.pmid: 22528793
references.citation: Mol Cell Proteomics. 2006 Nov;5(11):2060-71
references.pmid: 16861260
references.citation: J Clin Oncol. 1999 Nov;17(11):3631-52
references.pmid: 10550163
references.citation: Oncotarget. 2012 Feb;3(2):144-57
references.pmid: 22323550
references.citation: Clin Genet. 2011 Oct;80(4):305-18
references.pmid: 21651512
references.citation: J Neurochem. 2002 Jan;80(1):178-90
references.pmid: 11796756
references.citation: J Neurosci. 2006 Oct 4;26(40):10110-9
references.pmid: 17021167
references.citation: Nat Rev Drug Discov. 2007 Jul;6(7):541-55
references.pmid: 17585331
references.citation: Glia. 2001 Mar 15;33(4):298-305
references.pmid: 11246228
references.citation: Biochim Biophys Acta. 2010 Aug;1801(8):896-905
references.pmid: 20382260
references.citation: J Immunol. 2002 Apr 15;168(8):4087-4094
references.pmid: 11937568
references.citation: J Biol Chem. 2004 Jan 30;279(5):3862-8
references.pmid: 14585838
references.citation: J Immunol. 2008 Mar 1;180(5):3305-12
references.pmid: 18292555
references.citation: Physiol Rev. 2013 Jan;93(1):269-309
references.pmid: 23303910
references.citation: J Neurochem. 2001 Jan;76(2):391-400
references.pmid: 11208902
references.citation: Mol Ther. 2010 Jan;18(1):44-53
references.pmid: 19654569
references.citation: J Intern Med. 2011 Oct;270(4):377-87
references.pmid: 21486371
references.citation: J Biol Chem. 2004 Apr 2;279(14):14009-15
references.pmid: 14709547
references.citation: J Biol Chem. 2005 Jun 10;280(23):22212-21
references.pmid: 15817453
references.citation: Neuron. 2010 Nov 4;68(3):340-61
references.pmid: 21040840
references.citation: J Cell Sci. 2005 Mar 1;118(Pt 5):843-6
references.pmid: 15731001
references.citation: J Biol Chem. 2003 Jun 20;278(25):22980-8
references.pmid: 12686551
references.citation: Brain Res Rev. 2008 Jun;58(1):236-46
references.pmid: 18485483
references.citation: Genes Dev. 2005 Jan 1;19(1):1-49
references.pmid: 15630019
references.citation: J Neurosci. 2003 Feb 15;23(4):1119-24
references.pmid: 12598599
references.citation: Cold Spring Harb Perspect Biol. 2010 Feb;2(2):a001818
references.pmid: 20182621
references.citation: J Neurosci. 2010 Apr 28;30(17):6116-21
references.pmid: 20427669
references.citation: PLoS One. 2013 Jul 16;8(7):e68534
references.pmid: 23874659
references.citation: Dev Neurobiol. 2011 Jun;71(6):528-53
references.pmid: 21557504
references.citation: J Physiol. 2007 Mar 1;579(Pt 2):413-29
references.pmid: 17170046
references.citation: J Cardiovasc Pharmacol. 2008 Apr;51(4):388-95
references.pmid: 18427282
references.citation: Science. 1993 Jan 15;259(5093):377-81
references.pmid: 8380507
references.citation: Brain. 2012 Nov;135(Pt 11):3355-70
references.pmid: 23087045
references.citation: Proc Natl Acad Sci U S A. 2008 Aug 12;105(32):11394-9
references.pmid: 18685105
references.citation: Biochem Biophys Res Commun. 2004 Nov 12;324(2):835-9
references.pmid: 15474503
references.citation: J Neurosci Res. 1993 Aug 1;35(5):567-76
references.pmid: 8377226
references.citation: Biochem J. 1998 Aug 1;333 ( Pt 3):497-504
references.pmid: 9677305
references.citation: J Biol Chem. 2006 May 5;281(18):12799-808
references.pmid: 16524875
references.citation: J Intern Med. 2006 Dec;260(6):493-508
references.pmid: 17116000
references.citation: J Biol Chem. 2008 Sep 12;283(37):25150-25163
references.pmid: 18614539
references.citation: Proc Natl Acad Sci U S A. 2006 Mar 7;103(10):3869-74
references.pmid: 16505352
references.citation: Neurosci Lett. 1998 Apr 24;246(2):65-8
references.pmid: 9627181
references.citation: J Biol Chem. 2010 May 21;285(21):16369-77
references.pmid: 20348106
references.citation: Biochim Biophys Acta. 2003 Mar 10;1610(2):271-80
references.pmid: 12648780