Biosynthesis of 15-deoxy-∆-PGJ2 and the ligation of PPARγ

945 Introduction The PPAR nuclear hormone transcription factors heterodimerize with retinoic acid receptors to regulate expression of distinct gene cassettes (1, 2). Although three PPAR isotypes (α, δ, and γ) have been well characterized, the identity of their natural ligands remains controversial (3–6). PPARγ is expressed predominantly in adipose tissue, colon and macrophages, and to a lesser extent, in vascular smooth muscle cells (1–3). Among the genes regulated by PPARγ, many are involved in lipid metabolism, including lipoprotein lipase (LPL), adipocyte fatty acid binding protein (aP2), acyl-CoA synthase, and fatty acid transport protein (2, 3). Synthetic PPARγ agonists promote the maturation of fibroblasts to adipocytes in vitro (2, 3) and one class of such agonists, the glitazones, has been used in the treatment of diabetes. In addition, synthetic PPARγ agonists promote uptake of modified lipids by macrophages (7, 8) and may retard atherogenesis in mice (9). The increasing convergence of insulin resistance, obesity, and cardiovascular morbidity in the metabolic syndrome has further focused attention on the molecular mechanisms of PPARγ activation. PGs are formed through the sequential actions of COXs and a variety of PG synthases, which are expressed with some tissue specificity (10, 11). PGD2 is formed abundantly in the brain (12) and in mast cells (13). It undergoes spontaneous dehydration to PGJ2 in vitro, a reaction enhanced by albumininduced catalysis, which yields a number of additional derivatives, including 15-deoxy-∆-PGJ2 (15d-PGJ2) (14, 15). This compound, like other PGs (16), can be actively transported into cells (17). In contrast to conventional PGs, PGJ2 and its derivatives possess a highly reactive cyclopentenone (CP) ring (18), which permits them to ligate nuclear receptors and to modify intracellular signaling molecules. CPPGs exhibit biologic properties in vitro of potential relevance to inflammation, cellular proliferation, and differentiation (18, 19). In addition to its effects on adipocyte maturation, 15d-PGJ2 has been implicated in the PPARγ-dependent propagation (20) and resolution (21) of inflammation, and in the fibrotic reaction to activation of proteaseBiosynthesis of 15-deoxy-∆-PGJ2 and the ligation of PPARγ