Anti-adipogenesis by 6-thioinosine is mediated by downregulation of PPAR γ through JNK-dependent upregulation of iNOS
Anti-adipogenesis by 6-thioinosine is mediated by downregulation of PPAR γ through JNK-dependent upregulation of iNOS
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DOI：
10.1007/s00018-009-0196-y
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发表时间：
2010-02-01
影响因子：
8
通讯作者：
Park, Deokhoon
中科院分区：
文献类型：
--
作者：
Lee, Jongsung;Jung, Eunsun;Park, Deokhoon
脂肪细胞功能障碍与肥胖的发生有关。本研究表明，6-硫代肌苷抑制脂肪细胞分化。6-硫代肌苷可降低PPAR-γ和C/EBPα的mRNA水平，但不降低C/EBPβ和Delta的mRNA水平。此外，6-硫代肌苷下调PPAR-γ靶基因(LPL、CD36、aP2和LXRα)的mRNA水平。我们还证实了6-硫代肌苷抑制PPAR-γ的反式激活活性和mRNA水平。此外，试图阐明6-硫代肌苷介导的作用的可能机制表明，6-硫代肌苷诱导iNOS基因表达而不影响eNOS的表达，这是通过激活AP-1，特别是JNK介导的。此外，还发现6-硫代肌苷在JNK激活信号通路中位于Mekk-1的上游。综上所述，这些发现表明，6-硫代肌苷抑制脂肪细胞分化主要是通过减少PPAR-γ的表达，而PPAR-γ的表达是通过激活JNK上调iNOS而实现的。
Adipocyte dysfunction is associated with the development of obesity. This study shows that 6-thioinosine inhibits adipocyte differentiation. The mRNA levels of PPAR gamma and C/EBP alpha, but not C/EBP beta and delta, were reduced by 6-thioinosine. Moreover, the mRNA levels of PPAR gamma target genes (LPL, CD36, aP2, and LXR alpha) were down-regulated by 6-thioinosine. We also demonstrated that 6-thioinosine inhibits the transactivation activity and the mRNA level of PPAR gamma. Additionally, attempts to elucidate a possible mechanism underlying the 6-thioinosine-mediated effects revealed that 6-thioinosine induced iNOS gene expression without impacting eNOS expression, and that this was mediated through activation of AP-1, especially, JNK. In addition, 6-thioinosine was found to operate upstream of MEKK-1 in JNK activation signaling. Taken together, these findings suggest that the inhibition of adipocyte differentiation by 6-thioinosine occurs primarily through the reduced expression of PPAR gamma, which is mediated by upregulation of iNOS via the activation of JNK.