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Biosynthesis of 15-deoxy-Δ12,14-PGJ2 and the ligation of PPARγ
L. Chastine Bell-Parikh, … , Muredach Reilly, Garret A. FitzGerald
L. Chastine Bell-Parikh, … , Muredach Reilly, Garret A. FitzGerald
Published September 15, 2003
Citation Information: J Clin Invest. 2003;112(6):945-955. https://doi.org/10.1172/JCI18012.
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Article Cell biology

Biosynthesis of 15-deoxy-Δ12,14-PGJ2 and the ligation of PPARγ

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Abstract

15-deoxy-Δ12,14-PGJ2 (15d-PGJ2) has been identified as an endogenous ligand for PPARγ, inducing adipogenesis in vitro. Additional roles for this molecule in the propagation and resolution of inflammation, ligation of NF-κB, and mediation of apoptosis have been proposed. However, quantitative, physiochemical evidence for the formation of 15d-PGJ2 in vivo is lacking. We report that 15d-PGJ2 is detectable using liquid chromatography–mass spectrometry–mass spectrometry at low picomolar concentrations in the medium of 3T3-L1 preadipocytes. However, despite induction of COX-2, production of PGs, including 15d-PGJ2, does not increase during adipocyte differentiation, a process unaltered by COX inhibition. 15d-PGJ2 is detectable as a minor product of COX-2 in human urine. However, its biosynthesis is unaltered during or after COX activation in vivo by LPS. Furthermore, the biosynthesis of 15d-PGJ2 is not augmented in the joint fluid of patients with arthritis, nor is its urinary excretion increased in patients with diabetes or obesity. 15d-PGJ2 is not the endogenous mediator of PPARγ-dependent adipocyte activation and is unaltered in clinical settings in which PPARγ activation has been implicated.

Authors

L. Chastine Bell-Parikh, Tomomi Ide, John A. Lawson, Peter McNamara, Muredach Reilly, Garret A. FitzGerald

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Figure 2

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3T3-L1 cells were treated with DM or ciglitazone (15 μM) to initiate dif...
3T3-L1 cells were treated with DM or ciglitazone (15 μM) to initiate differentiation and were evaluated on days 8 or 10. (a) COX inhibition fails to modulate DM-induced adipocyte differentiation. The extent of TAG formation was estimated in cells differentiated with DM, ciglitazone (Cig), or DM in combination with indomethacin (3 μM) or NS-398 (10 μM). (b) PG formation is not enhanced during adipogenesis. Products during adipogenesis, as determined by Northern blotting (PPARγ, aP2, GAPDH), RT-PCR (COX-1), ribonuclease protection assay (COX-2) analysis, and LC-MS-MS (PGE2, 15d-PGJ2) in the medium (med) and cells. (c) Inhibition of PG formation by indomethacin fails to modulate the induction of adipocyte protein expression by DM. (d) Inhibition of PG formation fails to influence accumulation of lipid induced by DM. Oil red O staining of cells illustrates lipid accumulation in untreated cells versus cells treated with DM ± indomethacin. (e) 15d-PGJ2 drives adipogenesis in a PPARγ-dependent manner. Cells were treated with 15d-PGJ2 (0.1–15 μM) for 2 days in the absence (open circle) or presence (filled circle) of the PPARγ antagonist BADGE (100 μM). (f) Low concentrations of 15d-PGJ2 do not amplify the effect of ciglitazone. Cells were differentiated with ciglitazone alone (filled circle) or in combination with 1 μM (open circle) or 0.1 μM 15d-PGJ2 (filled triangle). (g) COX inhibition fails to modulate the enhancement of ciglitazone-dependent differentiation by DM. Cells were incubated to differentiate by adding ciglitazone alone (filled triangle) or in combination with DM (filled circle) or DM + indomethacin (open circle).

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