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Bioenergetic cues shift FXR splicing towards FXR alpha 2 to modulate hepatic lipolysis and fatty acid metabolism

2015-12Journal article Open access
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dc.contributor.authorCorreia, Jorge
dc.contributor.authorMassart, Julie
dc.contributor.authorde Boer, Jan Freark
dc.contributor.authorPorsmyr-Palmertz, Margareta
dc.contributor.authorMartinez-Redondo, Vicente
dc.contributor.authorAgudelo, Leandro Z.
dc.contributor.authorSinha, Indranil
dc.contributor.authorMeierhofer, David
dc.contributor.authorRibeiro, Vera
dc.contributor.authorBjornholm, Marie
dc.contributor.authorSauer, Sascha
dc.contributor.authorDahlman-Wright, Karin
dc.contributor.authorZierath, Juleen R.
dc.contributor.authorGroen, Albert K.
dc.contributor.authorRuas, Jorge L.
dc.date.accessioned2018-12-07T14:52:46Z
dc.date.available2018-12-07T14:52:46Z
dc.date.issued2015-12
dc.description.abstractObjective: Farnesoid X receptor (FXR) plays a prominent role in hepatic lipid metabolism. The FXR gene encodes four proteins with structural differences suggestive of discrete biological functions about which little is known. Methods: We expressed each FXR variant in primary hepatocytes and evaluated global gene expression, lipid profile, and metabolic fluxes. Gene delivery of FXR variants to Fxr(-/-) mouse liver was performed to evaluate their role in vivo. The effects of fasting and physical exercise on hepatic Fxr splicing were determined. Results: We show that FXR splice isoforms regulate largely different gene sets and have specific effects on hepatic metabolism. FXR alpha 2 (but not alpha 1) activates a broad transcriptional program in hepatocytes conducive to lipolysis, fatty acid oxidation, and ketogenesis. Consequently, FXR alpha 2 decreases cellular lipid accumulation and improves cellular insulin signaling to AKT. FXR alpha 2 expression in Fxr(-/-) mouse liver activates a similar gene program and robustly decreases hepatic triglyceride levels. On the other hand, FXRa1 reduces hepatic triglyceride content to a lesser extent and does so through regulation of lipogenic gene expression. Bioenergetic cues, such as fasting and exercise, dynamically regulate Fxr splicing in mouse liver to increase Fxr alpha 2 expression. Conclusions: Our results show that the main FXR variants in human liver (alpha 1 and alpha 2) reduce hepatic lipid accumulation through distinct mechanisms and to different degrees. Taking this novel mechanism into account could greatly improve the pharmacological targeting and therapeutic efficacy of FXR agonists. (C) 2015 The Authors. Published by Elsevier GmbH. This is an open access article under the CC BY-NC-ND license (http://creativecommons. org/licenses/by-nc-nd/4.0/).
dc.description.sponsorshipNovo Nordisk Fonden [NNF12OC1016062]; European Research Council [233285]
dc.description.versioninfo:eu-repo/semantics/publishedVersion
dc.identifier.doi10.1016/j.molmet.2015.09.005
dc.identifier.issn2212-8778
dc.identifier.urihttp://hdl.handle.net/10400.1/11203
dc.language.isoeng
dc.peerreviewedyes
dc.publisherElsevier Science
dc.relationDiscovery of Type 2 Diabetes Targets
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.subjectFarnesoid-X-receptor
dc.subjectAdipose triglyceride lipase
dc.subjectSalt export pump
dc.subjectHormone-sensitive lipase
dc.subjectNuclear receptor
dc.subjectLiver-Disease
dc.subjectInsulin-resistance
dc.subjectBile-acid
dc.subjectNonalcoholic steatohepatitis
dc.subjectObeticholic acid
dc.titleBioenergetic cues shift FXR splicing towards FXR alpha 2 to modulate hepatic lipolysis and fatty acid metabolism
dc.typejournal article
dspace.entity.typePublication
oaire.awardTitleDiscovery of Type 2 Diabetes Targets
oaire.awardURIinfo:eu-repo/grantAgreement/EC/FP7/233285/EU
oaire.citation.endPage902
oaire.citation.issue12
oaire.citation.startPage891
oaire.citation.titleMolecular Metabolism
oaire.citation.volume4
oaire.fundingStreamFP7
person.familyNameCorreia
person.familyNameRibeiro
person.givenNameJorge
person.givenNameVera
person.identifier.ciencia-id3411-732A-B7FB
person.identifier.orcid0000-0002-6377-9053
person.identifier.orcid0000-0002-9697-7830
person.identifier.ridG-3783-2011
person.identifier.scopus-author-id7006349364
project.funder.identifierhttp://doi.org/10.13039/501100008530
project.funder.nameEuropean Commission
rcaap.rightsopenAccess
rcaap.typearticle
relation.isAuthorOfPublication36d0b3a1-f200-472c-bdf3-eb808c001c6e
relation.isAuthorOfPublication3f188970-86bb-4815-afd8-e5e70f922fd9
relation.isAuthorOfPublication.latestForDiscovery36d0b3a1-f200-472c-bdf3-eb808c001c6e
relation.isProjectOfPublication52c8c5ff-0d1c-4969-b8b0-191e535e64d6
relation.isProjectOfPublication.latestForDiscovery52c8c5ff-0d1c-4969-b8b0-191e535e64d6

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