The human myeloperoxidase gene is regulated by LXR and PPARalpha ligands.
Myeloperoxidase (MPO) is an oxidant-generating enzyme expressed in macrophages and implicated in atherosclerosis and cholesterol homeostasis. LXRalpha and PPARalpha regulate genes involved in cholesterol metabolism and the inflammatory response in macrophages. Here, we examine the effect of LXR and PPARalpha ligands on MPO expression. LXR and PPARalpha, 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 PPARalpha ligand GW9578 downregulates MPO expression in GMCSF-macrophages, while upregulating in MCSF-macrophages. In contrast, the mouse MPO gene, which lacks the primate-specific AluRRE, is not regulated by LXR or PPARalpha ligands. These findings identify human MPO as a novel LXR and PPARalpha target gene, consistent with the role of these receptors in regulation of proinflammatory genes in macrophages.
Reynolds
Wanda F
WF
Sidney Kimmel Cancer Center, San Diego, CA 92121, USA. wreynolds@skcc.org
Kumar
Alan P
AP
Piedrafita
F Javier
FJ
D000818:Animals; D050197:Atherosclerosis / Q000378:metabolism; D001854:Bone Marrow Cells / Q000166:cytology / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D006845:Hydrocarbons, Fluorinated; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D000071518:Liver X Receptors; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D057093:Orphan Nuclear Receptors; D047493:PPAR alpha / Q000378:metabolism*; D009195:Peroxidase / Q000096:biosynthesis* / Q000235:genetics*; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D013449:Sulfonamides / Q000494:pharmacology; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
D004268:DNA-Binding Proteins; D006845:Hydrocarbons, Fluorinated; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D047493:PPAR alpha; D009195:Peroxidase; D018160:Receptors, Cytoplasmic and Nuclear; D013449:Sulfonamides; C000605213:NR1H3 protein, human; C000605214:Nr1h3 protein, mouse; C423915:T0901317; D005466:Fluorocarbons; D000096926:Benzenesulfonamides