RT Journal Article
SR Electronic
T1 Repression of the Nuclear Receptor Small Heterodimer Partner (SHP) by Steatotic Drugs and in Advanced Non-Alcoholic Fatty Liver Disease (NAFLD)
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP mol.114.096313
DO 10.1124/mol.114.096313
A1 Marta Benet
A1 Carla Guzman
A1 Sandra Pisonero-Vaquero
A1 M. Victoria Garcia-Mediavilla
A1 Sonia Sanchez-Campos
A1 M. Luz Martinez-Chantar
A1 M Teresa Donato
A1 Jose V. Castell
A1 Ramiro Jover
YR 2015
UL http://molpharm.aspetjournals.org/content/early/2015/01/22/mol.114.096313.abstract
AB The small heterodimer partner (SHP, NR0B2) is an atypical nuclear receptor that lacks 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 non-alcoholic fatty liver disease (NAFLD) on SHP expression, and to investigate the potential mechanisms. SHP was found repressed by steatotic drugs (valproate, doxycycline, tetracycline and cyclosporin A) in cultured hepatic cells, and in 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 co-localize between -340 and -509 bp of the SHP promoter and mutation of a predicted C/EBPα response element at -473 bp 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.