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Cholesterol 24S-Hydroxylase overexpression inhibits the liver X receptor (LXR) pathway by activating small guanosine triphosphate-binding proteins (sGTPases) in neuronal cells

2015-06Journal article Open access
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dc.contributor.authorMoutinho, Miguel
dc.contributor.authorNunes, Maria João
dc.contributor.authorGomes, Anita Q.
dc.contributor.authorGama, Maria João
dc.contributor.authorCedazo-Minguez, Angel
dc.contributor.authorRodrigues, C. M.
dc.contributor.authorBjörkhem, Ingemar
dc.contributor.authorRodrigues, Elsa
dc.date.accessioned2014-10-03T14:54:53Z
dc.date.available2014-10-03T14:54:53Z
dc.date.issued2015-06
dc.description.abstractThe 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.por
dc.identifier.citationMoutinho M, Nunes MJ, Gomes AQ, Gama MJ, Cedazo-Minguez A, Rodrigues CM, et al. Cholesterol 24S-Hydroxylase overexpression inhibits the liver X receptor (LXR) pathway by activating small guanosine triphosphate-binding proteins (sGTPases) in neuronal cells. Mol Neurobiol. 2015;51(3):1489-503.por
dc.identifier.doi10.1007/s12035-014-8828-0
dc.identifier.urihttp://hdl.handle.net/10400.21/3850
dc.language.isoengpor
dc.peerreviewedyespor
dc.publisherSpringerpor
dc.relation.publisherversionhttp://link.springer.com/article/10.1007%2Fs12035-014-8828-0por
dc.subjectNeurosciencespor
dc.subjectNeurobiologypor
dc.subjectCYP46A1por
dc.subjectCytochrome P450por
dc.subjectBrain metabolismpor
dc.subjectCholesterolpor
dc.subjectSmall GTPasespor
dc.subjectIsoprenoidspor
dc.subjectPrenylationpor
dc.subjectRhoApor
dc.titleCholesterol 24S-Hydroxylase overexpression inhibits the liver X receptor (LXR) pathway by activating small guanosine triphosphate-binding proteins (sGTPases) in neuronal cellspor
dc.typejournal article
dspace.entity.typePublication
oaire.citation.endPage1503pt_PT
oaire.citation.issue3pt_PT
oaire.citation.startPage1489pt_PT
oaire.citation.titleMolecular Neurobiologypor
oaire.citation.volume51pt_PT
rcaap.rightsrestrictedAccesspor
rcaap.typearticlepor

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