Impaired LXRα phosphorylation attenuates progression of fatty liver disease

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dc.contributor.authorBécares, Natalia
dc.contributor.authorGage, Matthew C.
dc.contributor.authorVoisin, Maud
dc.contributor.authorShrestha, Elina
dc.contributor.authorMartín-Gutiérrez, Lucía
dc.contributor.authorLiang, Ning
dc.contributor.authorLouie, Rikah
dc.contributor.authorPourcet, Benoît
dc.contributor.authorPello, Óscar M.
dc.contributor.authorLuong, Tu Vinh
dc.contributor.authorGoñi Irigoyen, Saioa
dc.contributor.authorPichardo-Almarza, César
dc.contributor.authorRøberg-Larsen, Hanne
dc.contributor.authorDíaz-Zuccarini, Vanessa
dc.contributor.authorSteffensen, Knut R.
dc.contributor.authorO’Brien, Alastair
dc.contributor.authorGarabedian, Michael J.
dc.contributor.authorRombouts, Krista
dc.contributor.authorTreuter, Eckardt
dc.contributor.authorPineda-Torra, Inés
dc.contributor.departmentCiencias de la Saludes_ES
dc.contributor.departmentOsasun Zientziakeu
dc.date.accessioned2024-04-25T15:21:31Z
dc.date.available2024-04-25T15:21:31Z
dc.date.issued2019
dc.date.updated2024-04-25T14:39:41Z
dc.description.abstractNon-alcoholic fatty liver disease (NAFLD) is a very common indication for liver transplantation. How fat-rich diets promote progression from fatty liver to more damaging inflammatory and fibrotic stages is poorly understood. Here, we show that disrupting phosphorylation at Ser196 (S196A) in the liver X receptor alpha (LXRα, NR1H3) retards NAFLD progression in mice on a high-fat-high-cholesterol diet. Mechanistically, this is explained by key histone acetylation (H3K27) and transcriptional changes in pro-fibrotic and pro-inflammatory genes. Furthermore, S196A-LXRα expression reveals the regulation of novel diet-specific LXRα-responsive genes, including the induction of Ces1f, implicated in the breakdown of hepatic lipids. This involves induced H3K27 acetylation and altered LXR and TBLR1 cofactor occupancy at the Ces1f gene in S196A fatty livers. Overall, impaired Ser196-LXRα phosphorylation acts as a novel nutritional molecular sensor that profoundly alters the hepatic H3K27 acetylome and transcriptome during NAFLD progression placing LXRα phosphorylation as an alternative anti-inflammatory or anti-fibrotic therapeutic target.en
dc.description.sponsorshipThis work was supported by a Medical Research Council New Investigator Grant G0801278 (I.P.-T.), British Heart Foundation Project Grants PG/13/10/30000 (I.P.-T.) and PG/16/87/32492 (M.C.G.), UCL Grand Challenges PhD Studentship (N.B. and I.P.-T.), Academy of Medical Sciences Newton Advanced Fellowship (I.P.-T.), Royal Free Charity (I.P.-T.), University of Oslo DIATECH@UiO initiative (H.R.-L.), the Centre for Innovative Medicine at the Karolinska Institute grant CIMED-2-391/2016 (E.T.), the Swedish Research Council grant VR-2016- 01743 (E.T.), the Swedish Cancer Society grant CAN-2015/609 (E.T.), the Swedish Diabetes Foundation grant DIA2016-157 (E.T.), the Novo Nordisk Foundation grant NN2017-21086 (E.T.), and the European Union FP7 HEALTH program grant HUMAN-F5-2013-602757 (E.T.). M.J.G. and M.V. were supported by NIH R01HL117226. C.P.-A. and V.D.-Z. received support by the EPSRC grant (EP/L000296/1) and the Leverhulme Trust Senior Research Fellowship (RF-2015-482) and V.D.-Z. by the Wellcome/EPSRC Centre for Interventional and Surgical Sciences grant (203145Z/16/Z).en
dc.format.mimetypeapplication/pdfen
dc.identifier.citationBecares, N., Gage, M. C., Voisin, M., Shrestha, E., Martin-Gutierrez, L., Liang, N., Louie, R., Pourcet, B., Pello, O. M., Luong, T. V., Goñi, S., Pichardo-Almarza, C., Røberg-Larsen, H., Diaz-Zuccarini, V., Steffensen, K. R., O¿Brien, A., Garabedian, M. J., Rombouts, K., Treuter, E., Pineda-Torra, I. (2019) Impaired LXR¿ phosphorylation attenuates progression of fatty liver disease. Cell Reports, 26(4), 984-995. https://doi.org/10.1016/j.celrep.2018.12.094.en
dc.identifier.doi10.1016/j.celrep.2018.12.094
dc.identifier.issn2211-1247
dc.identifier.urihttps://academica-e.unavarra.es/handle/2454/48037
dc.language.isoengen
dc.publisherCell Pressen
dc.relation.ispartofCell Reports 26(4), 2019, 984-995.e6en
dc.relation.publisherversionhttps://doi.org/10.1016/j.celrep.2018.12.094
dc.rights© 2019 The Authors. This is an open access article under the CC BY license.en
dc.rights.accessRightsinfo:eu-repo/semantics/openAccess
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectLiver X receptoren
dc.subjectPhosphorylationen
dc.subjectLiveren
dc.subjectLipid metabolismen
dc.subjectInflammationen
dc.subjectFibrosisen
dc.subjectTranscriptionen
dc.subjectNon-alcoholic fatty liver diseaseen
dc.titleImpaired LXRα phosphorylation attenuates progression of fatty liver diseaseen
dc.typeinfo:eu-repo/semantics/article
dc.type.versioninfo:eu-repo/semantics/publishedVersion
dspace.entity.typePublication
relation.isAuthorOfPublication7945ddd5-cf8b-4927-bd7a-4ade2fb61f11
relation.isAuthorOfPublication.latestForDiscovery7945ddd5-cf8b-4927-bd7a-4ade2fb61f11

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