ABNORMAL REGULATION OF HEPATIC GLUCOCORTICOID RECEPTOR MESSENGER-RNA AND RECEPTOR PROTEIN DISTRIBUTION IN THE OBESE ZUCKER RAT

This study examines the cellular distribution of glucocorticold recept or (GR) protein and transcriptional activity of the GR gene in the liv er of Zucker obese (fa/fa) rats, Immunoabsorption and Western blotting showed an increase in nuclear GR protein level but a decrease in cyto solic GR levels in the liver of 5-week old male obese rats (fa/fa) com pared to their lean littermates (Fa/-), These changes were confirmed b y receptor-ligand binding assays with [H-3]-dexamethasone which showed a sixfold increase in average obese nuclear GR binding and a twofold reduction in cytosolic GR binding, HSP90, but not HSP70, levels were r educed in hepatic cytosol and increased in hepatic nuclei prepared fro m obese rats, Using Northern blot analysis of hepatic RNA, we demonstr ated a twofold increase in hepatic mRNAs for GR, malic enzyme (ME), ty rosine aminotransferase (TAT), and glyceraldehyde 3-PO4-dehydrogenase in the obese rat. Increased transcription of GR and ME mRNAs in obese nuclei was indicated in nuclear run-on assays, These data suggest that there is increased nuclear localization of GR in the liver of obese r ats and suggests that increased transcription of the GR gene may contr ibute to this effect, The described changes may contribute to the abno rmal regulation by glucocorticoids of some hepatic genes in the Zucker fa/fa rat.