ASMase is required for chronic alcohol induced hepatic endoplasmic reticulum stress and mitochondrial cholesterol loading

PMCID: PMC3779525.-- et al.

Bibliographic Details
Authors: Fernández, Anna, Matías, Nuria, Fucho, Raquel, Ribas, Vicent, Montfort, Claudia von, Nuño-Lámbarri, Natalia, Baulies, Anna, Martínez, Laura, Tarrats, Núria, Marí, Montserrat, Colell Riera, Anna, Morales, Albert, Bataller, Ramón, García-Ruiz, Carmen, Fernández-Checa, José C.
Format: article
Status:Versión aceptada para publicación
Publication Date:2013
Country:España
Institution:Consejo Superior de Investigaciones Científicas (CSIC)
Repository:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/88438
Online Access:http://hdl.handle.net/10261/88438
Access Level:Open access
Keyword:ER stress
Mitochondrial cholesterol
Homocysteine
Alcohol induced liver disease
Ceramide
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spelling ASMase is required for chronic alcohol induced hepatic endoplasmic reticulum stress and mitochondrial cholesterol loadingFernández, AnnaMatías, NuriaFucho, RaquelRibas, VicentMontfort, Claudia vonNuño-Lámbarri, NataliaBaulies, AnnaMartínez, LauraTarrats, NúriaMarí, MontserratColell Riera, AnnaMorales, AlbertBataller, RamónGarcía-Ruiz, CarmenFernández-Checa, José C.ER stressMitochondrial cholesterolHomocysteineAlcohol induced liver diseaseCeramidePMCID: PMC3779525.-- et al.[Background & Aims]: The pathogenesis of alcohol-induced liver disease (ALD) is poorly understood. Here, we examined the role of acid sphingomyelinase (ASMase) in alcohol induced hepatic endoplasmic reticulum (ER) stress, a key mechanism of ALD. [Methods]: We examined ER stress, lipogenesis, hyperhomocysteinemia, mitochondrial cholesterol (mChol) trafficking and susceptibility to LPS and concanavalin-A in ASMase-/- mice fed alcohol. [Results]: Alcohol feeding increased SREBP-1c, DGAT-2, and FAS mRNA in ASMase+/+ but not in ASMase-/- mice. Compared to ASMase+/+ mice, ASMase-/- mice exhibited decreased expression of ER stress markers induced by alcohol, but the level of tunicamycin-mediated upregulation of ER stress markers and steatosis was similar in both types of mice. The increase in homocysteine levels induced by alcohol feeding was comparable in both ASMase+/+ and ASMase-/- mice. Exogenous ASMase, but not neutral SMase, induced ER stress by perturbing ER Ca2+ homeostasis. Moreover, alcohol-induced mChol loading and StARD1 overexpression were blunted in ASMase-/- mice. Tunicamycin upregulated StARD1 expression and this outcome was abrogated by tauroursodeoxycholic acid. Alcohol-induced liver injury and sensitization to LPS and concanavalin-A were prevented in ASMase-/- mice. These effects were reproduced in alcohol-fed TNFR1/R2-/- mice. Moreover, ASMase does not impair hepatic regeneration following partial hepatectomy. Of relevance, liver samples from patients with alcoholic hepatitis exhibited increased expression of ASMase, StARD1, and ER stress markers. [Conclusions]: Our data indicate that ASMase is critical for alcohol-induced ER stress, and provide a rationale for further clinical investigation in ALD. © 2013 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.The work was supported by CIBEREHD, Fundació la Marató de TV3, la Mutua Madrileña, and grants PI10/02114, PI09/0056 and PI09/1164 (Instituto de Salud Carlos III), SAF2008-02199, SAF2009-11417, SAF2010-15760, SAF2011-23031, SAF2012-34831, and BFU2010-18826 (Plan Nacional de I+D), Spain; and P50-AA-11999 (Research Center for Liver and Pancreatic Diseases, NIAAA/NIH).Peer ReviewedElsevierFundación Mutua MadrileñaInstituto de Salud Carlos IIIFundació La Marató de TV3Ministerio de Economía y Competitividad (España)National Institutes of Health (US)Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]2013201320132013info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Postprintinfo:eu-repo/semantics/acceptedVersionhttp://hdl.handle.net/10261/88438reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Ingléshttp://dx.doi.org/10.1016/j.jhep.2013.05.023Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/884382026-05-22T06:33:51Z
dc.title.none.fl_str_mv ASMase is required for chronic alcohol induced hepatic endoplasmic reticulum stress and mitochondrial cholesterol loading
title ASMase is required for chronic alcohol induced hepatic endoplasmic reticulum stress and mitochondrial cholesterol loading
spellingShingle ASMase is required for chronic alcohol induced hepatic endoplasmic reticulum stress and mitochondrial cholesterol loading
Fernández, Anna
ER stress
Mitochondrial cholesterol
Homocysteine
Alcohol induced liver disease
Ceramide
title_short ASMase is required for chronic alcohol induced hepatic endoplasmic reticulum stress and mitochondrial cholesterol loading
title_full ASMase is required for chronic alcohol induced hepatic endoplasmic reticulum stress and mitochondrial cholesterol loading
title_fullStr ASMase is required for chronic alcohol induced hepatic endoplasmic reticulum stress and mitochondrial cholesterol loading
title_full_unstemmed ASMase is required for chronic alcohol induced hepatic endoplasmic reticulum stress and mitochondrial cholesterol loading
title_sort ASMase is required for chronic alcohol induced hepatic endoplasmic reticulum stress and mitochondrial cholesterol loading
dc.creator.none.fl_str_mv Fernández, Anna
Matías, Nuria
Fucho, Raquel
Ribas, Vicent
Montfort, Claudia von
Nuño-Lámbarri, Natalia
Baulies, Anna
Martínez, Laura
Tarrats, Núria
Marí, Montserrat
Colell Riera, Anna
Morales, Albert
Bataller, Ramón
García-Ruiz, Carmen
Fernández-Checa, José C.
author Fernández, Anna
author_facet Fernández, Anna
Matías, Nuria
Fucho, Raquel
Ribas, Vicent
Montfort, Claudia von
Nuño-Lámbarri, Natalia
Baulies, Anna
Martínez, Laura
Tarrats, Núria
Marí, Montserrat
Colell Riera, Anna
Morales, Albert
Bataller, Ramón
García-Ruiz, Carmen
Fernández-Checa, José C.
author_role author
author2 Matías, Nuria
Fucho, Raquel
Ribas, Vicent
Montfort, Claudia von
Nuño-Lámbarri, Natalia
Baulies, Anna
Martínez, Laura
Tarrats, Núria
Marí, Montserrat
Colell Riera, Anna
Morales, Albert
Bataller, Ramón
García-Ruiz, Carmen
Fernández-Checa, José C.
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Fundación Mutua Madrileña
Instituto de Salud Carlos III
Fundació La Marató de TV3
Ministerio de Economía y Competitividad (España)
National Institutes of Health (US)
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv ER stress
Mitochondrial cholesterol
Homocysteine
Alcohol induced liver disease
Ceramide
topic ER stress
Mitochondrial cholesterol
Homocysteine
Alcohol induced liver disease
Ceramide
description PMCID: PMC3779525.-- et al.
publishDate 2013
dc.date.none.fl_str_mv 2013
2013
2013
2013
dc.type.none.fl_str_mv info:eu-repo/semantics/article
http://purl.org/coar/resource_type/c_6501
Postprint
info:eu-repo/semantics/acceptedVersion
format article
status_str acceptedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/88438
url http://hdl.handle.net/10261/88438
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv http://dx.doi.org/10.1016/j.jhep.2013.05.023
Sí
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv Elsevier
publisher.none.fl_str_mv Elsevier
dc.source.none.fl_str_mv reponame:DIGITAL.CSIC. Repositorio Institucional del CSIC
instname:Consejo Superior de Investigaciones Científicas (CSIC)
instname_str Consejo Superior de Investigaciones Científicas (CSIC)
reponame_str DIGITAL.CSIC. Repositorio Institucional del CSIC
collection DIGITAL.CSIC. Repositorio Institucional del CSIC
repository.name.fl_str_mv
repository.mail.fl_str_mv
_version_ 1869406612618215424
score 15.812429

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