Endocrine Abstracts

Synthetic glucocorticoids (GCs) including dexamethasone (Dex) are potent anti-inflammatory drugs. However, long-term use of GCs results in deleterious side effects such as hyperglycemia, hepatosteatosis, and insulin resistance. The nuclear hormone receptors LXRα and LXRβ are known for their important roles in modulating whole-body cholesterol homeostasis. Recently, we have shown that liver X receptor β (LXRβ) knockout mice are protected against Dex-induced hyperglycemia and hepatosteatosis, without affecting Dex-mediated inflammatory suppression (Patel et al. J Clin Invest, 2011). From our studies, we proposed a model whereby upon GR activation, hepatic LXRβ is required to achieve maximal induction of the gluconeogenic pathway in the liver but is not required for GR-mediated suppression of the immune system. To determine whether the interplay between LXRβ and GR could be exploited for future therapeutic intervention, we tested whether LXRβ antagonists would mimic the LXRβ−/− phenotype in this context. GSK2033, a potent pan-LXR antagonist, was dosed to LXRα−/− primary hepatocytes and/or mice alone or in combination with Dex. Herein, we show that antagonizing LXRβ activity (by GSK2033) along with Dex co-administration reduced Dex-dependent Pepck induction and glucose production in primary hepatocytes. Moreover, in situ perfusion of GSK2033 and Dex via the portal vein decreased GR and Pol II recruitment to the Pepck promoter in LXRα−/− livers. In addition, Dex-mediated inflammatory suppression remained unaffected by GSK2033 co-treatment in mouse primary macrophages stimulated with LPS. These findings demonstrate that the undesired metabolic effects of therapeutic GCs might be avoided by concurrent pharmacologic antagonism of hepatic LXRβ; without affecting the desired anti-inflammatory effects of GCs.