Peroxisome proliferator-activated receptor alpha induces NADPH oxidase activity in macrophages, leading to the generation of LDL with PPAR-alpha activation properties.
Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors controlling lipid and glucose metabolism as well as inflammation. PPARs are expressed in macrophages, cells that also generate reactive oxygen species (ROS). In this study, we investigated whether PPARs regulate ROS production in macrophages. Different PPAR-alpha, but not PPAR-gamma agonists, increased the production of ROS (H2O2 and ) in human and murine macrophages. PPAR-alpha activation did not induce cellular toxicity, but significantly decreased intracellular glutathione levels. The increase in ROS production was not attributable to inherent prooxidant effects of the PPAR-alpha agonists tested, but was mediated by PPAR-alpha, because the effects were lost in bone marrow-derived macrophages from PPAR-alpha-/- mice. The PPAR-alpha-induced increase in ROS was attributable to the induction of NADPH oxidase, because (1) preincubation with the NADPH oxidase inhibitor diphenyleneiodinium prevented the increase in ROS production; (2) PPAR-alpha agonists increased production measured by superoxide dismutase-inhibitable cytochrome c reduction; (3) PPAR-alpha agonists induced mRNA levels of the NADPH oxidase subunits p47(phox), p67phox, and gp91phox and membrane p47phox protein levels; and (4) induction of ROS production was abolished in p47phox-/- and gp91phox-/- macrophages. Finally, induction of NADPH oxidase by PPAR-alpha agonists resulted in the formation of oxidized LDL metabolites that exert PPAR-alpha-independent proinflammatory and PPAR-alpha-dependent decrease of lipopolysaccharide-induced inducible nitric oxide synthase expression in macrophages. These data identify a novel mechanism of autogeneration of endogenous PPAR-alpha ligands via stimulation of NADPH oxidase activity.
Teissier
Elisabeth
E
UR 545 INSERM-Institut Pasteur de Lille and Faculté de Pharmacie, Université de Lille II, Lille, France.
Nohara
Atsushi
A
Chinetti
Giulia
G
Paumelle
Réjane
R
Cariou
Bertrand
B
Fruchart
Jean-Charles
JC
Brandes
Ralf P
RP
Shah
Ajay
A
Staels
Bart
B
D000818:Animals; D004789:Enzyme Activation / Q000187:drug effects; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D007249:Inflammation; D008077:Lipoproteins, LDL / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000502:physiology*; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000201:enzymology / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000187:drug effects; D019255:NADPH Oxidases / Q000096:biosynthesis* / Q000235:genetics; D019001:Nitric Oxide Synthase / Q000096:biosynthesis / Q000235:genetics; D052247:Nitric Oxide Synthase Type II; D047493:PPAR alpha / Q000819:agonists / Q000502:physiology*; D011743:Pyrimidines / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism*
D008077:Lipoproteins, LDL; D047493:PPAR alpha; D011743:Pyrimidines; D017382:Reactive Oxygen Species; C099252:oxidized low density lipoprotein; C006253:pirinixic acid; C496319:NOS2 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D019255:NADPH Oxidases; D005978:Glutathione