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Dipeptidyl Peptidase-4 Is a Pro-Recovery Mediator During Acute Hepatotoxic Damage and Mirrors Severe Shifts in Kupffer Cells

2018-09-07Journal article Open access
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dc.contributor.authorDuarte, Nádia
dc.contributor.authorCoelho, Inês
dc.contributor.authorHolovanchuk, Denys
dc.contributor.authorInês Almeida, Joana
dc.contributor.authorPenha-Gonçalves, Carlos
dc.contributor.authorPaula Macedo, Maria
dc.date.accessioned2018-09-25T13:30:13Z
dc.date.available2018-09-25T13:30:13Z
dc.date.issued2018-09-07
dc.descriptionThis deposit is composed by the main article plus the supplementary materials of the publication.pt_PT
dc.description.abstractDipeptidyl peptidase-4 (DPP-4 or clusters of differentiation [CD]26) is a multifunctional molecule with established roles in metabolism. Pharmacologic inhibition of DPP-4 is widely used to improve glycemic control through regulation of the incretin effect. Colaterally, CD26/DPP-4 inhibition appears to be beneficial in many inflammatory conditions, namely in delaying progression of liver pathology. Nevertheless, the exact implications of CD26/DPP-4 enzymatic activity in liver dysfunction remain unclear. In this work, we investigated the involvement of CD26/DPP-4 in experimental mouse models of induced hepatocyte damage that severely impact Kupffer cell (KC) populations. Liver dysfunction was evaluated in CD26 knockout (KO) and B6 wild-type mice during acute liver damage induced by acetaminophen, chronic liver damage induced by carbon tetrachloride, and KC-depleting treatment with clodronate-loaded liposomes. We found that necrosis resolution after hepatotoxic injury was delayed in CD26KO mice and in B6 mice treated with the CD26/DPP-4 inhibitor sitagliptin, suggesting that DPP-4 enzymatic activity plays a role in recovering from acute liver damage. Interestingly, the severe KC population reduction in acute and chronic liver injury was concomitant with increased CD26/DPP-4 serum levels. Remarkably, both chronic liver damage and noninflammatory depletion of KCs by clodronate liposomes were marked by oscillation in CD26/DPP-4 serum activity that mirrored the kinetics of liver KC depletion/recovery. Conclusion:CD26/DPP-4 enzymatic activity contributes to necrosis resolution during recovery from acute liver injury. Serum CD26/DPP-4 is elevated when severe perturbations are imposed on KC populations, regardless of patent liver damage. We propose that serum CD26/DPP-4 is a potential systemic surrogate marker of severe impairments in the KC population imposed by clinical and subclinical liver conditions.pt_PT
dc.description.sponsorshipFundingSupported by the Fundação para a Ciência e Tecnologia (grant no. PTDC/BIM‐MET/0486/2012), iNOVA4Health (UID/Multi/04462/2013), the European Commission Marie Skłodowska‐Curie Actions H2020 (grant agreements no. 722619 and no. 734719), the Sociedade Portuguesa de Diabetologia Bolsa Charneco da Costa 2017, and a Fundação para a Ciência e Tecnologia fellowship no. PD/BD/105997/2014 to I.C.pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationDuarte, N. , Coelho, I. , Holovanchuk, D. , Inês Almeida, J. , Penha‐Gonçalves, C. and Paula Macedo, M. (2018), Dipeptidyl Peptidase‐4 Is a Pro‐Recovery Mediator During Acute Hepatotoxic Damage and Mirrors Severe Shifts in Kupffer Cells. Hepatology Communications, 2: 1080-1094. doi:10.1002/hep4.1225pt_PT
dc.identifier.doi10.1002/hep4.1225pt_PT
dc.identifier.urihttp://hdl.handle.net/10400.7/895
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.relationBioenergetic Remodeling in the Pathophysiology and Treatment of Non-Alcoholic Fatty Liver Disease
dc.relationmitoFOIE GRAS: Non-invasive Profiling of Mitochondrial Function in Non-Alcoholic Fatty Liver Disease
dc.relationPROGRAMA DOUTORAL EM BIOLOGIA INTEGRATIVA E BIOMEDICINA IBB 2015 - Deciphering the role of macrophages in liver fibrogenesis, fibrosis regression and tissue repair
dc.relationCD26/DPP4 in Fatty Liver Disease progression: inflammation impinges on dysmetabolism.
dc.relation.publisherversionhttps://aasldpubs.onlinelibrary.wiley.com/doi/abs/10.1002/hep4.1225pt_PT
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/pt_PT
dc.subjectDipeptidyl Peptidase‐4pt_PT
dc.subjectHepatotoxicpt_PT
dc.subjectKupffer Cellspt_PT
dc.subjectCD26/DPP-4pt_PT
dc.titleDipeptidyl Peptidase-4 Is a Pro-Recovery Mediator During Acute Hepatotoxic Damage and Mirrors Severe Shifts in Kupffer Cellspt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.awardTitleBioenergetic Remodeling in the Pathophysiology and Treatment of Non-Alcoholic Fatty Liver Disease
oaire.awardTitlemitoFOIE GRAS: Non-invasive Profiling of Mitochondrial Function in Non-Alcoholic Fatty Liver Disease
oaire.awardTitlePROGRAMA DOUTORAL EM BIOLOGIA INTEGRATIVA E BIOMEDICINA IBB 2015 - Deciphering the role of macrophages in liver fibrogenesis, fibrosis regression and tissue repair
oaire.awardTitleCD26/DPP4 in Fatty Liver Disease progression: inflammation impinges on dysmetabolism.
oaire.awardURIinfo:eu-repo/grantAgreement/EC/H2020/722619/EU
oaire.awardURIinfo:eu-repo/grantAgreement/EC/H2020/734719/EU
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/OE/PD%2FBD%2F105997%2F2014/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/3599-PPCDT/PTDC%2FBIM-MET%2F0486%2F2012/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/5876/UID%2FMulti%2F04462%2F2013/PT
oaire.citation.endPage1094pt_PT
oaire.citation.issue9pt_PT
oaire.citation.startPage1080pt_PT
oaire.citation.titleHepatology Communicationspt_PT
oaire.citation.volume2pt_PT
oaire.fundingStreamH2020
oaire.fundingStreamH2020
oaire.fundingStreamOE
oaire.fundingStream3599-PPCDT
oaire.fundingStream5876
project.funder.identifierhttp://doi.org/10.13039/501100008530
project.funder.identifierhttp://doi.org/10.13039/501100008530
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.nameEuropean Commission
project.funder.nameEuropean Commission
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
rcaap.rightsopenAccesspt_PT
rcaap.typearticlept_PT
relation.isProjectOfPublication54177e5e-6ddc-44f4-9529-b59f4e3bacd4
relation.isProjectOfPublication58165a78-8802-4b31-a236-b1a1546c87cb
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relation.isProjectOfPublication.latestForDiscovery54177e5e-6ddc-44f4-9529-b59f4e3bacd4

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