title: Repression of the nuclear receptor small heterodimer partner by steatotic drugs and in advanced nonalcoholic fatty liver disease.
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.
authors.affiliation: 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.).
authors.forename: Marta
authors.initials: M
authors.lastname: Benet
authors.affiliation: 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.).
authors.forename: Carla
authors.initials: C
authors.lastname: Guzmán
authors.affiliation: 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.).
authors.forename: Sandra
authors.initials: S
authors.lastname: Pisonero-Vaquero
authors.affiliation: 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.).
authors.forename: M Victoria
authors.initials: MV
authors.lastname: García-Mediavilla
authors.affiliation: 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.).
authors.forename: Sonia
authors.initials: S
authors.lastname: Sánchez-Campos
authors.affiliation: 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.).
authors.forename: M Luz
authors.initials: ML
authors.lastname: Martínez-Chantar
authors.affiliation: 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.).
authors.forename: M Teresa
authors.initials: MT
authors.lastname: Donato
authors.affiliation: 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.).
authors.forename: José Vicente
authors.initials: JV
authors.lastname: Castell
authors.affiliation: 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.) ramiro.jover@uv.es.
authors.forename: Ramiro
authors.initials: R
authors.lastname: Jover
mesh_terms: D000818:Animals; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D016572:Cyclosporine / Q000633:toxicity; D004318:Doxycycline / Q000633:toxicity; D005234:Fatty Liver / Q000139:chemically induced / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D065626:Non-alcoholic Fatty Liver Disease / Q000209:etiology / Q000378:metabolism; D011401:Promoter Regions, Genetic; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013752:Tetracycline / Q000633:toxicity; D013841:Thiazepines / Q000633:toxicity; D014158:Transcription, Genetic; D014635:Valproic Acid / Q000633:toxicity
chemical_list: D022763:CCAAT-Enhancer-Binding Protein-alpha; D018160:Receptors, Cytoplasmic and Nuclear; D013841:Thiazepines; C099713:nuclear receptor subfamily 0, group B, member 2; C050504:tianeptine; D014635:Valproic Acid; D016572:Cyclosporine; D019950:Mitogen-Activated Protein Kinase 1; D013752:Tetracycline; D004318:Doxycycline