Oleic acid-induced ADRP expression requires both AP-1 and PPAR response elements, and is reduced by Pycnogenol through mRNA degradation in NMuLi liver cells
Oleic acid-induced ADRP expression requires both AP-1 and PPAR response elements, and is reduced by Pycnogenol through mRNA degradation in NMuLi liver cells
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DOI：
10.1152/ajpendo.00119.2009
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发表时间：
2009-07-01
影响因子：
5.1
通讯作者：
Nishimura, Junji
中科院分区：
文献类型：
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作者：
Fan, Bin;Ikuyama, Shoichiro;Nishimura, Junji
Fan B，Ikuyama S，Gu JQ，Wei P，Oyama J，Inoguchi T，Nishimura J.油酸诱导的ADRP表达需要AP-1和PPAR反应元件，并通过NMuLi肝细胞中的mRNA降解被碧萝芷降低。Am J Physiol Endocrinol Metab 297：E112-E123，2009.首次发表于2009年4月21日; doi：10.1152/ajpendo.00119.2009.-脂肪酸刺激脂质蓄积，同时增加肝细胞中脂肪分化相关蛋白（ADRP）的表达。虽然通常认为脂肪酸对ADRP表达的影响是由过氧化物酶体增殖物激活受体（PPARs）介导的，但我们在此使用NMuLi小鼠肝脏非实质细胞系确定了另一种分子机制，该细胞系表达PPAR γ和δ，但不表达α。油酸（OA）和PPAR γ和-δ的特异性配体刺激ADRP表达以及~ 2，090-bp ADRP启动子活性，其包括邻近Ets/激活蛋白（AP）-1位点的PPAR应答元件（PPRE）。当AP-1位点发生突变时，尽管存在PPRE，OA仍不能刺激活性，而PPAR γ和-δ的配体确实刺激了活性，并且在共表达PPAR α的情况下，PPAR α配体也是如此。OA刺激AP-1的DNA结合，但不刺激PPAR配体。因为我们先前证明了碧萝芷（PYC），一种法国海洋松树皮提取物，部分通过抑制AP-1活性来抑制巨噬细胞中的ADRP表达，所以我们测试了PYC对NMuLi细胞的作用。PYC降低OA诱导的ADRP表达，沿着抑制脂滴形成。然而，PYC既不抑制OA刺激的ADRP启动子活性，也不抑制AP-1的DNA结合，而是降低ADRP mRNA的半衰期。所有这些结果表明，OA对ADRP表达的影响需要AP-1以及PPRE，PYC通过促进mRNA降解部分抑制ADRP表达。PYC是一种广泛使用的膳食补充剂，可能有助于预防脂质过度积聚，如肝脂肪变性。
Fan B, Ikuyama S, Gu JQ, Wei P, Oyama J, Inoguchi T, Nishimura J. Oleic acid-induced ADRP expression requires both AP-1 and PPAR response elements, and is reduced by Pycnogenol through mRNA degradation in NMuLi liver cells. Am J Physiol Endocrinol Metab 297: E112-E123, 2009. First published April 21, 2009; doi: 10.1152/ajpendo.00119.2009.-Fatty acids stimulate lipid accumulation in parallel with increased expression of adipose differentiation-related protein ( ADRP) in liver cells. Although it is generally considered that the fatty acid effect on ADRP expression is mediated by peroxisome proliferator-activated receptors (PPARs), we identified here an additional molecular mechanism using the NMuLi mouse liver nonparenchymal cell line, which expresses PPAR gamma and delta but not alpha. Oleic acid (OA) and specific ligands for PPAR gamma and -delta stimulated ADRP expression as well as the -2,090-bp ADRP promoter activity which encompasses the PPAR response element (PPRE) adjacent to an Ets/activator protein (AP)-1 site. When the AP-1 site was mutated, OA failed to stimulate the activity despite the presence of the PPRE, whereas ligands for PPAR gamma and -delta did stimulate it and so did a PPAR alpha ligand under the coexpression of PPAR alpha. DNA binding of AP-1 was stimulated by OA but not by PPAR ligands. Because we previously demonstrated that Pycnogenol (PYC), a French maritime pine bark extract, suppressed ADRP expression in macrophages partly by suppression of AP-1 activity, we tested the effect of PYC on NMuLi cells. PYC reduced the OA-induced ADRP expression along with suppression of lipid droplet formation. However, PYC neither suppressed the OA-stimulated ADRP promoter activity nor DNA binding of AP-1 but, instead, reduced the ADRP mRNA half-life. All these results indicate that the effect of OA on ADRP expression requires AP-1 as well as PPRE, and PYC suppresses the ADRP expression in part by facilitating mRNA degradation. PYC, a widely used dietary supplement, could be beneficial for the prevention of excessive lipid accumulation such as hepatic steatosis.