Statins synergize dexamethasone-induced adipocyte fatty acid binding protein expression in macrophages

Abstract

Objective: Macrophage adipocyte fatty acid binding protein (FABP4) plays an important role in the development of atherosclerosis. We previously reported that dexamethasone induces macrophage FABP4 mRNA expression. Statins inhibit FABP4 expression. However, it remains unknown that if statins can antagonise dexamethasone-induced macrophage FABP4 expression.

Methods and results: We determined the effect of co-treatment of statins and dexamethasone on macrophage FABP4 expression. Unexpectedly, statins did not block the induction of macrophage FABP4 expression by dexamethasone. In contrast, statins synergized dexamethasone-induced FABP4 expression. In vivo, pitavastatin synergized dexamethasone-induced FABP4 expression in both peritoneal macrophages and adipose tissues. Cholesterol and mevalonate, but not farnesylation and geranylgeranylation, inhibited the synergistic induction. Promoter assay disclosed a putative negative glucocorticoid regulatory element (nGRE) in FABP4 gene. Pitavastatin had little effect on expression of glucocorticoid receptor (GR). However, pitavastatin enhanced dexamethasone-mediated GR nuclear translocation but inhibited the binding of GR with nGRE.

Conclusion: Our study defines an important mechanism involved in the regulation of macrophage FABP4 expression by a glucocorticoid and statins.