Separating the Anti-Inflammatory and Diabetogenic Effects of Glucocorticoids Through LXRβ Antagonism.
Synthetic glucocorticoids (GCs), including dexamethasone (DEX), are powerful anti-inflammatory drugs. Long-term use of GCs, however, can result in metabolic side effects such as hyperglycemia, hepatosteatosis, and insulin resistance. The GC receptor (GR) and liver X receptors (LXRα and LXRβ) regulate overlapping genes involved in gluconeogenesis and inflammation. We have previously shown that Lxrβ-/- mice are resistant to the diabetogenic effects of DEX but still sensitive to its immunosuppressive actions. To determine whether this finding could be exploited for therapeutic intervention, we treated mice with GSK2033, a pan-LXR antagonist, alone or combined with DEX. GSK2033 suppressed GC-induced gluconeogenic gene expression without affecting immune-responsive GR target genes. The suppressive effect of GSK2033 on DEX-induced gluconeogenic genes was specific to LXRβ, was liver cell autonomous, and occurred in a target gene-specific manner. Compared with DEX treatment alone, the coadministration of GSK2033 with DEX decreased the recruitment of GR and its accessory factors MED1 and C/EBPβ to the phosphoenolpyruvate carboxykinase promoter. However, GSK2033 had no effect on DEX-mediated suppression of inflammatory genes expressed in the liver or in mouse primary macrophages stimulated with lipopolysaccharides. In conclusion, our study provides evidence that the gluconeogenic and immunosuppressive actions of GR activation can be mechanistically dissociated by pharmacological antagonism of LXRβ. Treatment with an LXRβ antagonist could allow the safer use of existing GC drugs in patients requiring chronic dosing of anti-inflammatory agents for the treatment of diseases such as rheumatoid arthritis and inflammatory bowel disease.
Department of Pharmaceutical Sciences, University of Toronto, Toronto, Ontario M5S 3M2, Canada.
Rucha
R
Patel
Department of Pharmaceutical Sciences, University of Toronto, Toronto, Ontario M5S 3M2, Canada.
Lilia
L
Magomedova
Department of Pharmaceutical Sciences, University of Toronto, Toronto, Ontario M5S 3M2, Canada.
Ricky
R
Tsai
Department of Pharmaceutical Sciences, University of Toronto, Toronto, Ontario M5S 3M2, Canada.
Stéphane
S
Angers
Department of Chemistry, York University, Toronto, Ontario M3J 1P3, Canada.
Arturo
A
Orellana
Department of Pharmaceutical Sciences, University of Toronto, Toronto, Ontario M5S 3M2, Canada.|Banting and Best Diabetes Centre, University of Toronto, Toronto, Ontario M5G 2C4, Canada.
Carolyn L
CL
Cummins
D000818:Animals; D003907:Dexamethasone / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects*; D005938:Glucocorticoids / Q000494:pharmacology*; D005943:Gluconeogenesis / Q000235:genetics*; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D007249:Inflammation / Q000235:genetics* / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D000071518:Liver X Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051379:Mice; D011965:Receptors, Glucocorticoid / Q000378:metabolism*; D013449:Sulfonamides / Q000494:pharmacology; D000096926:Benzenesulfonamides
D003907:Dexamethasone; D005938:Glucocorticoids; D000071518:Liver X Receptors; D011965:Receptors, Glucocorticoid; D013449:Sulfonamides; C549350:2,4,6-trimethyl-N-((3'-(methylsulfonyl)-4-biphenylyl)methyl)-N-((5-(trifluoromethyl)-2-furanyl)methyl)benzenesulfonamide; D000096926:Benzenesulfonamides