Departament de Fisiologia, Facultat de Farmàcia, Universitat de Barcelona, Barcelona, Spain.
Departament de Fisiologia, Facultat de Farmàcia, Universitat de Barcelona, Barcelona, Spain
Am J Physiol Gastrointest Liver Physiol. 2014 Sep 15;307(6):G664-71. doi: 10.1152/ajpgi.00064.2014. Epub 2014 Jul 17.
Cyclooxygenases (COXs) and lipoxygenases (LOXs) are important enzymes that metabolize arachidonic and linoleic acids. Various metabolites generated by the arachidonic acid cascade regulate cell proliferation, apoptosis, differentiation, and senescence. Hydroxyoctadecadienoic acids (HODEs) are synthesized from linoleic acid, giving two enantiomeric forms for each metabolite. The aim was to investigate the effect of 13-HODE enantiomers on nondifferentiated Caco-2 cell growth/apoptosis. Our results indicate that 13(S)-HODE decreases cell growth and DNA synthesis of nondifferentiated Caco-2 cells cultured with 10% fetal bovine serum (FBS). Moreover, 13(S)-HODE showed an apoptotic effect that was reduced in the presence of a specific peroxisome proliferator-activated receptor-γ (PPARγ) antagonist. In addition, we observed that 13(S)-HODE but not 13(R)-HODE is a ligand to PPARγ, confirming the implication of this nuclear receptor in 13(S)-HODE actions. In contrast, 13(R)-HODE increases cell growth and DNA synthesis in the absence of FBS. 13(R)-HODE interaction with BLT receptors activates ERK and CREB signaling pathways, as well as PGE2 synthesis. These results suggest that the proliferative effect of 13(R)-HODE could be due, at least in part, to COX pathway activation. Thus both enantiomers use different receptors and have contrary effects. We also found these differential effects of 9-HODE enantiomers on cell growth/apoptosis. Therefore, the balance between (R)-HODEs and (S)-HODEs in the intestinal epithelium could be important to its cell growth/apoptosis homeostasis.
环氧化酶（COXs）和脂氧合酶（LOXs）是代谢花生四烯酸和亚油酸的重要酶。花生四烯酸级联产生的各种代谢物调节细胞增殖、凋亡、分化和衰老。羟基十八碳二烯酸（HODEs）是从亚油酸合成的，每种代谢物都有两种对映体形式。本研究旨在探讨 13-HODE 对未分化 Caco-2 细胞生长/凋亡的影响。结果表明，在含有 10%胎牛血清（FBS）的培养基中，13(S)-HODE 可降低未分化 Caco-2 细胞的生长和 DNA 合成。此外，13(S)-HODE 表现出凋亡作用，而在存在特定过氧化物酶体增殖物激活受体-γ（PPARγ）拮抗剂的情况下，该作用会降低。此外，我们观察到 13(S)-HODE 而非 13(R)-HODE 是 PPARγ 的配体，证实了该核受体在 13(S)-HODE 作用中的作用。相反，13(R)-HODE 在没有 FBS 的情况下增加细胞生长和 DNA 合成。13(R)-HODE 与 BLT 受体相互作用可激活 ERK 和 CREB 信号通路以及 PGE2 的合成。这些结果表明，13(R)-HODE 的增殖作用至少部分归因于 COX 途径的激活。因此，两种对映体使用不同的受体并产生相反的作用。我们还发现 9-HODE 对映体对细胞生长/凋亡的这些差异作用。因此，肠上皮细胞中 (R)-HODE 和 (S)-HODE 之间的平衡可能对其细胞生长/凋亡的稳态很重要。
