Statins synergize dexamethasone‐induced macrophage aP2 expression _ A dual glucocorticoid receptor‐dependent mechanism

Statins synergize dexamethasone‐induced macrophage aP2 expression _A dual glucocorticoid receptor‐dependent mechanism aP2, a cytoplasmic protein involved in cellular transport and metabolism of fatty acids, is expressed by macrophages. Lack of aP2 expression or aP2 inhibitor prevents high‐fat diet‐induced atherosclerosis. Dexamethasone is a major component of adipogenic differentiating agents. In contrast, statins inhibit adipocyte differentiation. However, the interplay between dexamethasone and statins on macrophage aP2 expression is unknown. Here we report that although dexamethasone increased while statins decreased aP2 protein expression moderately, unexpectedly, statins synergized dexamethasone‐induced aP2 protein expression. aP2 mRNA levels were also elevated by both in a synergistic manner suggesting the regulation is transcriptional. In addition, the synergistic induction was observed with peritoneal macrophages indicating the physiological relevance. Cholesterol and mevalonate, but not farnesylation and geranylgeranylation, inhibited the synergistic induction. Promoter analysis disclosed that induction of aP2 expression by dexamethasone was glucocorticoid receptor (GR)‐dependent. In addition, we found a putative negative glucocorticoid regulatory element (nGRE) in aP2 gene. Pitavastatin had little effect on expression of GR, but enhanced dexamethasone‐mediated nuclear translocation of GR and inhibited the binding of GR to nGRE that resulted in an enhanced binding of GR to the positive GRE in aP2 gene and a synergistic induction of aP2 expression. Our study, for the first time, discloses the complex of mechanisms involved in regulation of macrophage aP2 expression in response to the agents against inflammation and hypercholesterolemia.