OR23-2 Molecular crosstalk between GR and hepatic liver x receptor β (LXRβ) in glucocorticoid induced hyperglycemia

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: OR23-Metabolic & Stress Receptors in Energy Homeostasis
Basic
Sunday, June 16, 2013: 11:15 AM-12:45 PM
Presentation Start Time: 11:30 AM
Room 256 (Moscone Center)
Rucha H Patel*1, Ricky Tsai1, Arturo Orellana2 and Carolyn L Cummins1
1University of Toronto, Toronto, ON, Canada, 2York University, Toronto, ON, Canada
Introduction:

Glucocorticoid (GC) levels are elevated in patients with type 2 diabetes and in diabetic mouse models. Synthetic GCs, such as dexamethasone (dex), are potent anti-inflammatory drugs; however, long term use results in deleterious side effects such as hyperglycemia, hepatosteatosis, and insulin resistance. GR, LXRα and LXRβ are nuclear hormone receptors that regulate overlapping genes controlling gluconeogenesis, lipogenesis and inflammation. Recently, our lab has shown that the whole body LXRβ−∕− mice are protected against GC-induced hyperglycemia and hepatosteatosis (Patel, R. et al., JCI 2011). Several key questions remained and are addressed below. 1) Is the loss of LXRβ only in the liver sufficient for the attenuation of GC-induced side effects? (2)  Do LXRβ and GR function in a protein complex? (3) Can pharmacologic antagonism of LXRβ in combination with GC therapy recapitulate the same effects as genetic loss of function?

 Results: Herein, we show that dex treatment (5 mg/kg, bid, 5d) of control (LXRβfl/fl) and liver specific LXRβ knockout  (AlbCreLXRβfl/fl ; liv.LXRβ−∕−) mice caused hyperglycemia only in control mice but not in the liv.LXRβ−∕− mice. Co-IP studies in H4IIE cells showed that a direct or indirect physical interaction exists between LXRβ and GR. In agreement with in-vivo studies, time course studies in primary hepatocytes demonstrated that dex treatment caused potent induction of Pepck mRNA in WT but not LXRβ−∕− hepatocytes. Interestingly, antagonizing LXRβ activity (with GSK2033) along with dex co- administration reduced Pepck induction and glucose production in primary hepatocytes. Moreover, GSK 2033 and dex co-perfusion stabilized LXRβ, while decreasing Pol II recruitment to the Pepck promoter in LXRα−∕− and WT mice livers. GSK2033 had no effect on dex mediated suppression of inflammatory genes stimulated in mouse primary macrophages.

Conclusion: GC treatment in liv.LXRβ-/- mice confirmed that protection against GC-induced hyperglycemia was due to hepatic expression of LXRβ and not altered hormonal regulation in other metabolic organs, which may be present in the whole-body knockouts. Furthermore, the combination of LXR antagonist and dex treatment also demonstrated that the deleterious side-effects of GC might be avoided by selectively modulating LXR activity while preserving the desired anti-inflammatory effects.

(1) Patel R et al., JCI 2011; January; 121(1): 431–441

Nothing to Disclose: RHP, RT, AO, CLC

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm

Sources of Research Support: This work is supported by the Natural Sciences and Engineering Research Council of Canada NSERC RGPIN 356873-08 (CLC), the Canadian Institutes of Health Research CIHR-MOP-97904 (CLC)