Oxidized alkyl phospholipids are specific, high affinity peroxisome proliferator-activated receptor gamma ligands and agonists

Synthetic high affinity peroxisome proliferator-activated receptor (PPAR) a gonists are known, but biologic ligands are of low affinity. Oxidized low d ensity lipoprotein (oxLDL) is inflammatory and signals through PPARs. We sh owed, by phospholipase A(1) digestion, that PPAR gamma agonists in oxLDL ar ise from the small pool of alkyl phosphatidylcholines in LDL. We identified an abundant oxidatively fragmented alkyl phospholipid in oxLDL, hexadecyl azelaoyl phosphatidylcholine (azPC), as a high affinity ligand and agonist for PPAR gamma. [H-3]azPC bound recombinant PPAR gamma with an affinity (K- d(app) approximate to 40 nM) that was equivalent to rosiglitazone (BRL49653 ), and competition with rosiglitazone showed that binding occurred in the l igand-binding pocket. azPC induced PPRE reporter gene expression, as did ro siglitazone, with a half-maximal effect at 100 nM. Over-expression of PPAR alpha or PPAR gamma revealed that azPC was a specific PPAR gamma agonist. T he scavenger receptor CD36 is encoded by a PPRE-responsive gene, and azPC e nhanced expression of CD36 in primary human monocytes. We found that anti-C D36 inhibited azPC uptake, and it inhibited PPRE reporter induction. Result s with a small molecule phospholipid flippase mimetic suggest azPC acts int racellularly and that cellular azPC accumulation was efficient. Thus, certa in alkyl phospholipid oxidation products in oxLDL are specific, high affini ty extracellular ligands and agonists for PPAR gamma that induce PPAR-respo nsive genes.