Glucocorticoids Stimulate Hepatic and Renal Catecholamine Inactivation by Direct Rapid Induction of the Dopamine Sulfotransferase Sult1d1

Abstract

During the stress response and metabolic fasting, glucocorticoids acting via the glucocorticoid receptor (GR) stimulate hepatic glucose production by activating specific gluconeogenic enzyme target genes. To characterize novel direct GR-regulated hepatic target genes under glucocorticoid control, we performed a whole genome gene expression microarray using dexamethasone-treated GR-null mice. Strongly induced previously characterized genes included phosphoenolpyruvate carboxykinase, serine dehydratase, tyrosine oxygenase, lipin 1, metallothionine, and cdkn1A. Novel induced genes included Ddit4, Fkbp5, Megf9, Sult1e1, and Sult1d1, and all were verified by real-time PCR. Sult1d1, a sulfotransferase, is a member of a large superfamily of detoxification enzymes and has an important role in the inactivation of endogenous dopamine-derived compounds, including the catecholamines. Treatment of primary mouse hepatocytes with dexamethasone for 6 h dramatically increased Sult1d1 mRNA levels, whereas cotreatment with RU-486, a GR antagonist, blocked induction by dexamethasone. Sult1d1 mRNA levels were also increased by dexamethasone in the kidney, a major site of Sult1d1 synthesis. Sult1d1 mRNA was localized by in situ hybridization to renal collecting ducts and was rapidly induced by glucocorticoids in renal inner medullary collecting duct (IMCD3) cells. Hepatic and renal Sult1d1 enzymatic activity was significantly induced in vivo in wild-type mice 6 h after dexamethasone treatment. Chromatin immunoprecipitation assay analysis upstream of the Sult1d1 gene promoter identified a glucocorticoid response element close to the neighboring glucocorticoid-responsive estrogen sulfotransferase Sult1e1 gene, indicating that both genes potentially share a common glucocorticoid response element. These results suggest that Sult1d1 in mice is directly induced by glucocorticoids and may attenuate elevated catecholamine activity during the stress response.

SETDB2 Links Glucocorticoid to Lipid Metabolism through Insig2a Regulation

“…The most down-regulated genes in the sh-DB2 cells corresponded to known Dex-responsive GR targets, such as Tat and Cyp2b10 . When we compared the SETDB2-regulated genes to GR target genes identified by comparison of wild type and a liver knockout of GR (Wong et al, 2010) there were 34 Dex-induced genes that overlapped (36%; 34 of the 95) (Fig. 2A).…”

The Human Blood Metabolome-Transcriptome Interface

“…Via binding to the glucocorticoid nuclear receptor (GR, official gene symbol NR3C1 ), it regulates various cellular processes like carbohydrate metabolism and the immune system by direct activation of target genes [40]. Remarkably, DDIT4 was identified as a GR target gene in mouse hepatocytes [41], rat hippocampus [42] and also in human peripheral blood lymphocytes [43] delivering a potential explanation of an indirect association for the observed correlation. Another GR target gene associated to cortisol is Suppressor Of Cytokine Signaling 1 ( SOCS1 , ρ = 0.36, p-value = 2.19 × 10 −23 ), a major constituent of the cytokine signaling pathway and inflammatory response [44].…”

Aldosterone-Specific Activation of Cardiomyocyte Mineralocorticoid Receptor In Vivo

“…Corticosterone administration did not alter body, heart, and kidney weight (Table S4). Corticosterone treatment similarly increased corticosteronemia (2-to 3-fold; P<0.05; Table S4) and hepatic expression of Sult1d1 (a glucocorticoid regulated gene) 21 in Ctrl and MR-cardio mice (P<0.05; Figure S7). Corticosterone also altered cardiac expression of Adamts4 and Trpc4 in MR-Cardio mice ( Figure S8).…”