Biosynthesis of 15-deoxy-Δ12,14-PGJ2 and the litigation of PPARγ
Biosynthesis of 15-deoxy-Δ12,14-PGJ2 and the litigation of PPARγ
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DOI：
10.1172/jci200318012
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发表时间：
2003-09-01
影响因子：
15.9
通讯作者：
FitzGerald, GA
中科院分区：
文献类型：
--
作者：
Bell-Parikh, LC;Ide, T;FitzGerald, GA
15 - 脱氧 - Δ(12,14) - 前列腺素J₂(15d - PGJ₂)已被确定为过氧化物酶体增殖物激活受体γ(PPARγ)的一种内源性配体，可在体外诱导脂肪生成。还提出该分子在炎症的传播和消退、核因子 - κB的连接以及细胞凋亡的介导中具有其他作用。然而，缺乏15d - PGJ₂在体内形成的定量物理化学证据。我们报道，使用液相色谱 - 串联质谱法可在3T3 - L1前脂肪细胞的培养基中检测到低皮摩尔浓度的15d - PGJ₂。然而，尽管诱导了环氧化酶 - 2(COX - 2)，但在脂肪细胞分化过程中，包括15d - PGJ₂在内的前列腺素(PGs)的产生并未增加，且这一过程不受COX抑制剂的影响。15d - PGJ₂可作为人尿液中环氧化酶 - 2的一种次要产物被检测到。然而，在体内由脂多糖(LPS)激活COX期间或之后，其生物合成未发生改变。此外，15d - PGJ₂在关节炎患者的关节液中的生物合成没有增加，在糖尿病或肥胖患者中其尿排泄也没有增加。15d - PGJ₂不是PPARγ依赖性脂肪细胞激活的内源性介质，并且在涉及PPARγ激活的临床环境中未发生改变。
15-deoxy-Delta(12,14)-PGJ(2) (15d-PGJ(2)) has been identified as an enclogenous ligand for PPARgamma, inducing adipogenesis in vitro. Additional roles for this molecule in the propagation and resolution of inflammation, ligation of NF-kappaB, and mediation of apoptosis have been proposed. However, quantitative physiochemical evidence for the formation of 15d-PGJ(2) in vivo is lacking. We report that 15d-PGJ(2) 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-PGJ(2), does not increase during adipocyte differentiation, a process unaltered by COX inhibition. 15d-PGJ(2) 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-PGJ(2) is not augmented in the joint fluid of patients with arthritis, nor is its urinary excretion increased in patients with diabetes or obesity. 15d-PGJ(2) is not the endogenous mediator of PPARgamma-dependent adipocyte activation and is unaltered in clinical settings in which PPARgamma activation has been implicated.