Myeloperoxidase (MPO) is an oxidant-generating enzyme expressed in macrophages and implicated in atherosclerosis and cholesterol homeostasis. LXR alpha and PPAR alpha regulate genes involved in cholesterol metabolism and the inflammatory response in macrophages. Here, we examine the effect of LXR and PPAR alpha ligands on MPO expression. LXR and PPAR alpha, as heterodimers with RXR, are shown to bind overlapping sites in an Alu receptor response element (AluRRE) in the MPO promoter. The LXR ligand T0901317 suppresses MPO mRNA expression in primary human macrophages, and in bone marrow cells and macrophages from huMPO transgenic mice. The PPAR alpha ligand GW9578 downregulates MPO expression in GMCSF-macrophages, while upregulating in MCSF-macrophages. In contrast, the mouse MPO gene, which lacks the prim ate-specific AluRRE, is not regulated by LXR or PPAR alpha ligands. These findings identify human MPO as a novel LXR and PPAR alpha target gene, consistent with the role of these receptors in regulation of proinflammatory genes in macrophages. (c) 2006 Elsevier Inc. All rights reserved.