TY - JOUR T1 - Repression of the Nuclear Receptor Small Heterodimer Partner by Steatotic Drugs and in Advanced Nonalcoholic Fatty Liver Disease JF - Molecular Pharmacology JO - Mol Pharmacol SP - 582 LP - 594 DO - 10.1124/mol.114.096313 VL - 87 IS - 4 AU - Marta Benet AU - Carla Guzmán AU - Sandra Pisonero-Vaquero AU - M. Victoria García-Mediavilla AU - Sonia Sánchez-Campos AU - M. Luz Martínez-Chantar AU - M. Teresa Donato AU - José Vicente Castell AU - Ramiro Jover Y1 - 2015/04/01 UR - http://molpharm.aspetjournals.org/content/87/4/582.abstract N2 - 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. ER -