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Research ArticleArticle

Repression of the Nuclear Receptor Small Heterodimer Partner by Steatotic Drugs and in Advanced Nonalcoholic Fatty Liver Disease

Marta Benet, Carla Guzmán, Sandra Pisonero-Vaquero, M. Victoria García-Mediavilla, Sonia Sánchez-Campos, M. Luz Martínez-Chantar, M. Teresa Donato, José Vicente Castell and Ramiro Jover
Molecular Pharmacology April 2015, 87 (4) 582-594; DOI: https://doi.org/10.1124/mol.114.096313
Marta Benet
Experimental Hepatology Unit, IIS Hospital La Fe, Valencia (M.B., C.G., M.T.D., J.V.C., R.J.); CIBERehd, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Barcelona (M.B., M.V.G.-M., S.S.-C., M.L.M.-C., M.T.D., J.V.C., R.J.); Institute of Biomedicine, University of León, León (S.P.-V., M.V.G.-M., S.S.-C.); CIC bioGUNE, Technology Park of Bizkaia, Derio (M.L.M.-C.); and Department of Biochemistry and Molecular Biology, University of Valencia, Valencia, Spain (M.T.D., J.V.C., R.J.)
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Carla Guzmán
Experimental Hepatology Unit, IIS Hospital La Fe, Valencia (M.B., C.G., M.T.D., J.V.C., R.J.); CIBERehd, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Barcelona (M.B., M.V.G.-M., S.S.-C., M.L.M.-C., M.T.D., J.V.C., R.J.); Institute of Biomedicine, University of León, León (S.P.-V., M.V.G.-M., S.S.-C.); CIC bioGUNE, Technology Park of Bizkaia, Derio (M.L.M.-C.); and Department of Biochemistry and Molecular Biology, University of Valencia, Valencia, Spain (M.T.D., J.V.C., R.J.)
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Sandra Pisonero-Vaquero
Experimental Hepatology Unit, IIS Hospital La Fe, Valencia (M.B., C.G., M.T.D., J.V.C., R.J.); CIBERehd, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Barcelona (M.B., M.V.G.-M., S.S.-C., M.L.M.-C., M.T.D., J.V.C., R.J.); Institute of Biomedicine, University of León, León (S.P.-V., M.V.G.-M., S.S.-C.); CIC bioGUNE, Technology Park of Bizkaia, Derio (M.L.M.-C.); and Department of Biochemistry and Molecular Biology, University of Valencia, Valencia, Spain (M.T.D., J.V.C., R.J.)
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M. Victoria García-Mediavilla
Experimental Hepatology Unit, IIS Hospital La Fe, Valencia (M.B., C.G., M.T.D., J.V.C., R.J.); CIBERehd, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Barcelona (M.B., M.V.G.-M., S.S.-C., M.L.M.-C., M.T.D., J.V.C., R.J.); Institute of Biomedicine, University of León, León (S.P.-V., M.V.G.-M., S.S.-C.); CIC bioGUNE, Technology Park of Bizkaia, Derio (M.L.M.-C.); and Department of Biochemistry and Molecular Biology, University of Valencia, Valencia, Spain (M.T.D., J.V.C., R.J.)
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Sonia Sánchez-Campos
Experimental Hepatology Unit, IIS Hospital La Fe, Valencia (M.B., C.G., M.T.D., J.V.C., R.J.); CIBERehd, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Barcelona (M.B., M.V.G.-M., S.S.-C., M.L.M.-C., M.T.D., J.V.C., R.J.); Institute of Biomedicine, University of León, León (S.P.-V., M.V.G.-M., S.S.-C.); CIC bioGUNE, Technology Park of Bizkaia, Derio (M.L.M.-C.); and Department of Biochemistry and Molecular Biology, University of Valencia, Valencia, Spain (M.T.D., J.V.C., R.J.)
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M. Luz Martínez-Chantar
Experimental Hepatology Unit, IIS Hospital La Fe, Valencia (M.B., C.G., M.T.D., J.V.C., R.J.); CIBERehd, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Barcelona (M.B., M.V.G.-M., S.S.-C., M.L.M.-C., M.T.D., J.V.C., R.J.); Institute of Biomedicine, University of León, León (S.P.-V., M.V.G.-M., S.S.-C.); CIC bioGUNE, Technology Park of Bizkaia, Derio (M.L.M.-C.); and Department of Biochemistry and Molecular Biology, University of Valencia, Valencia, Spain (M.T.D., J.V.C., R.J.)
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M. Teresa Donato
Experimental Hepatology Unit, IIS Hospital La Fe, Valencia (M.B., C.G., M.T.D., J.V.C., R.J.); CIBERehd, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Barcelona (M.B., M.V.G.-M., S.S.-C., M.L.M.-C., M.T.D., J.V.C., R.J.); Institute of Biomedicine, University of León, León (S.P.-V., M.V.G.-M., S.S.-C.); CIC bioGUNE, Technology Park of Bizkaia, Derio (M.L.M.-C.); and Department of Biochemistry and Molecular Biology, University of Valencia, Valencia, Spain (M.T.D., J.V.C., R.J.)
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José Vicente Castell
Experimental Hepatology Unit, IIS Hospital La Fe, Valencia (M.B., C.G., M.T.D., J.V.C., R.J.); CIBERehd, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Barcelona (M.B., M.V.G.-M., S.S.-C., M.L.M.-C., M.T.D., J.V.C., R.J.); Institute of Biomedicine, University of León, León (S.P.-V., M.V.G.-M., S.S.-C.); CIC bioGUNE, Technology Park of Bizkaia, Derio (M.L.M.-C.); and Department of Biochemistry and Molecular Biology, University of Valencia, Valencia, Spain (M.T.D., J.V.C., R.J.)
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Ramiro Jover
Experimental Hepatology Unit, IIS Hospital La Fe, Valencia (M.B., C.G., M.T.D., J.V.C., R.J.); CIBERehd, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Barcelona (M.B., M.V.G.-M., S.S.-C., M.L.M.-C., M.T.D., J.V.C., R.J.); Institute of Biomedicine, University of León, León (S.P.-V., M.V.G.-M., S.S.-C.); CIC bioGUNE, Technology Park of Bizkaia, Derio (M.L.M.-C.); and Department of Biochemistry and Molecular Biology, University of Valencia, Valencia, Spain (M.T.D., J.V.C., R.J.)
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Abstract

The small heterodimer partner (SHP) (NR0B2) is an atypical nuclear receptor that lacks a DNA-binding domain. It interacts with and inhibits many transcription factors, affecting key metabolic processes, including bile acid, cholesterol, fatty acid, and drug metabolism. Our aim was to determine the influence of steatotic drugs and nonalcoholic fatty liver disease (NAFLD) on SHP expression and investigate the potential mechanisms. SHP was found to be repressed by steatotic drugs (valproate, doxycycline, tetracycline, and cyclosporin A) in cultured hepatic cells and the livers of different animal models of NAFLD: iatrogenic (tetracycline-treated rats), genetic (glycine N-methyltransferase–deficient mice), and nutritional (mice fed a methionine- and choline-deficient diet). Among the different transcription factors investigated, CCAAT-enhancer-binding protein α (C/EBPα) showed the strongest dominant-repressive effect on SHP expression in HepG2 and human hepatocytes. Reporter assays revealed that the inhibitory effect of C/EBPα and steatotic drugs colocalize between −340 and −509 base pair of the SHP promoter, and mutation of a predicted C/EBPα response element at −473 base pair abolished SHP repression by both C/EBPα and drugs. Moreover, inhibition of major stress signaling pathways demonstrated that the mitogen-activated protein kinase kinase 1/2 pathway activates, while the phosphatidylinositol 3 kinase pathway represses SHP in a C/EBP-dependent manner. We conclude that SHP is downregulated by several steatotic drugs and in advanced NAFLD. These conditions can activate signals that target C/EBPα and consequently repress SHP, thus favoring the progression and severity of NAFLD.

Footnotes

    • Received October 8, 2014.
    • Accepted January 9, 2015.
  • This work has been partly supported by Grants PI-13/01470 and PI-11/01588 from Fondo de Investigación Sanitaria (FIS) (Instituto de Salud Carlos III), Grant BFU2013-48141-R from Programa Estatal de Investigación (Ministerio de Economía y Competitividad), Grant LE135U13 from Consejería de Educación (Junta de Castilla y León), and Grant ETORTEK-2012/Sanidad Gobierno Vasco 2013. M.B. and M.V.G.M were recipients of CIBERehd contracts [EHD-10-DOC2 and EHD-24-DOC], respectively. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

  • dx.doi.org/10.1124/mol.114.096313.

  • Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 87 (4)
Molecular Pharmacology
Vol. 87, Issue 4
1 Apr 2015
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Research ArticleArticle

SHP Repression by C/EBPα in Drug-Induced Steatosis

Marta Benet, Carla Guzmán, Sandra Pisonero-Vaquero, M. Victoria García-Mediavilla, Sonia Sánchez-Campos, M. Luz Martínez-Chantar, M. Teresa Donato, José Vicente Castell and Ramiro Jover
Molecular Pharmacology April 1, 2015, 87 (4) 582-594; DOI: https://doi.org/10.1124/mol.114.096313

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Research ArticleArticle

SHP Repression by C/EBPα in Drug-Induced Steatosis

Marta Benet, Carla Guzmán, Sandra Pisonero-Vaquero, M. Victoria García-Mediavilla, Sonia Sánchez-Campos, M. Luz Martínez-Chantar, M. Teresa Donato, José Vicente Castell and Ramiro Jover
Molecular Pharmacology April 1, 2015, 87 (4) 582-594; DOI: https://doi.org/10.1124/mol.114.096313
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