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Research ArticleGastrointestinal, Hepatic, Pulmonary, and Renal

Retinol-Binding Protein 4 and Peroxisome Proliferator-Activated Receptor-γ in Steatotic Liver Transplantation

Araní Casillas-Ramírez, Izabel Alfany-Fernández, Marta Massip-Salcedo, M. Emília Juan, Joana M. Planas, Anna Serafín, Mercè Pallàs, Antoni Rimola, Juan Rodés and Carmen Peralta
Journal of Pharmacology and Experimental Therapeutics July 2011, 338 (1) 143-153; DOI: https://doi.org/10.1124/jpet.110.177691
Araní Casillas-Ramírez
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Izabel Alfany-Fernández
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Marta Massip-Salcedo
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M. Emília Juan
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Joana M. Planas
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Anna Serafín
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Mercè Pallàs
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Antoni Rimola
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Juan Rodés
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Carmen Peralta
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Abstract

Numerous steatotic livers are discarded for transplantation because of their poor tolerance of ischemia-reperfusion (I/R). The injurious effects of retinol-binding protein 4 (RBP4) in various pathologies are well documented. RBP4 levels are reduced by peroxisome proliferator-activated receptor-γ (PPARγ) agonists. Strategies aimed at increasing PPARγ protect steatotic livers under warm ischemia. Ischemic preconditioning (PC) based on brief periods of I/R protects steatotic liver grafts against I/R injury, but the responsible mechanism is poorly understood. We examined the roles of RBP4 and PPARγ in I/R injury associated with steatotic liver transplantation and the benefits of PC in such situations. We report that RBP4 and PPARγ expression levels in nonsteatotic livers were similar to those found in the sham group. However, reduced RBP4 and increased PPARγ levels were observed in steatotic livers. Treatment with either RBP4 or a PPARγ antagonist was effective only in steatotic livers. PC, which increased RBP4 levels, and RBP4 treatment both reduced PPARγ levels and hepatic injury in steatotic livers. When PPARγ was activated, neither RBP4 treatment nor PC (despite RBP4 induction) protected steatotic livers. In conclusion, steatotic liver grafts are more predisposed to down-regulate RBP4 and overexpress PPARγ. RBP4 treatment and PC, through RBP4 induction, reduced PPARγ levels in steatotic liver grafts, thus protecting them from the PPARγ detrimental effects.

Footnotes

  • This research was supported by the Ministerio de Sanidad y Consumo (Madrid, Spain) [Project Grant PI060021]; the Ministerio de Ciencia e Innovación (Madrid, Spain) [Project Grant BFU2009-07410]; and the ACC1Ó (Barcelona, Spain) [Project Grant VALTEC08-2-0033]. A.C.-R. received a fellowship from the Agència de Gestió d'Ajuts Universitaris i de Recerca (Barcelona, Spain).

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

    doi:10.1124/jpet.110.177691.

  • ABBREVIATIONS:

    I/R
    ischemia-reperfusion
    RBP4
    retinol-binding protein 4
    PPARγ
    peroxisome proliferator-activated receptor-γ
    PC
    ischemic preconditioning
    AMPK
    AMP-activated protein kinase
    Ob
    obese
    Ln
    lean
    UW
    University of Wisconsin
    GW9662
    2-chloro-5-nitro-N-phenylbenzamide
    rosiglitazone
    (RS)-5-[4-(2-[methyl(pyridin-2-yl)amino]ethoxy)benzyl]thiazolidine-2,4-dione
    AICAR
    aminoimidazole-4-carboxamide ribonucleoside
    AST
    aspartate aminotransferase
    ALT
    alanine aminotransferase
    TR
    transplantation
    PCR
    polymerase chain reaction
    ED50
    median effective dose.

  • Received December 3, 2010.
  • Accepted April 8, 2011.
  • Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 338 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 338, Issue 1
1 Jul 2011
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Research ArticleGastrointestinal, Hepatic, Pulmonary, and Renal

Retinol-Binding Protein 4 and Peroxisome Proliferator-Activated Receptor-γ in Steatotic Liver Transplantation

Araní Casillas-Ramírez, Izabel Alfany-Fernández, Marta Massip-Salcedo, M. Emília Juan, Joana M. Planas, Anna Serafín, Mercè Pallàs, Antoni Rimola, Juan Rodés and Carmen Peralta
Journal of Pharmacology and Experimental Therapeutics July 1, 2011, 338 (1) 143-153; DOI: https://doi.org/10.1124/jpet.110.177691

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Research ArticleGastrointestinal, Hepatic, Pulmonary, and Renal

Retinol-Binding Protein 4 and Peroxisome Proliferator-Activated Receptor-γ in Steatotic Liver Transplantation

Araní Casillas-Ramírez, Izabel Alfany-Fernández, Marta Massip-Salcedo, M. Emília Juan, Joana M. Planas, Anna Serafín, Mercè Pallàs, Antoni Rimola, Juan Rodés and Carmen Peralta
Journal of Pharmacology and Experimental Therapeutics July 1, 2011, 338 (1) 143-153; DOI: https://doi.org/10.1124/jpet.110.177691
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