Activation of the Glucocorticoid Receptor or Liver X Receptors Interferes with Growth Hormone-Induced akr1b7 Gene Expression in Rat Hepatocytes

Abstract

AbstractThe akr1b7 gene encodes an aldo-keto reductase involved in detoxification of isocaproaldehyde, the product from side chain cleavage of cholesterol, and of 4-hydroxynonenal (4-HNE) formed by lipid peroxidation and cleavage. Here we show that the expression of akr1b7 mRNA in rat liver is sexually differentiated, expressed in females but not in males, and regulated by the sexually dimorphic secretion pattern of GH. A GH dose-dependent induction of akr1b7 was demonstrated in cultured primary rat hepatocytes, which was sensitive to cycloheximide. Activation of the glucocorticoid receptor (GR) or liver X receptors (LXR) by dexamethasone (Dex) and T1317, respectively, attenuated the GH-induced expression of akr1b7 and CYP2C12, the prototypical rat hepatic gene dependent on the female-characteristic secretion pattern of GH. In contrast, neither Dex nor T1317 had any repressive effect on the GH induction of IGF-I mRNA. A common mechanism for LXR- and GR-mediated repressive actions on gene transcription is inhibition of nuclear factor (NF)-κB; however, EMSAs and pharmacological interference with NF-κB signaling provided no evidence for the involvement of NF-κB in the repressive action of Dex and T1317 on GH-induced akr1b7 expression.