Borrelidin Isolated from Streptomyces sp. Inhibited Adipocyte Differentiation in 3T3-L1 Cells via Several Factors Including GATA-Binding Protein 3.
Borrelidin Isolated from Streptomyces sp. Inhibited Adipocyte Differentiation in 3T3-L1 Cells via Several Factors Including GATA-Binding Protein 3.
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DOI：
10.1248/bpb.b15-00257
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发表时间：
2015-10
影响因子：
2
通讯作者：
Hirotaka Matsuo;Y. Kondo;T. Kawasaki;S. Tokuyama;N. Imamura
中科院分区：
文献类型：
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作者：
Hirotaka Matsuo;Y. Kondo;T. Kawasaki;S. Tokuyama;N. Imamura
3 T3-L1脂肪细胞分化的抑制剂是从链霉菌属TK 08330中分离的，并通过光谱法鉴定为18元大环内酯疏螺旋体素。用1.0 μM疏螺旋体素处理抑制了80%的细胞内脂质积聚，并抑制了脂肪细胞特异性基因的表达。疏螺旋体素抑制脂肪细胞分化的两个主要调节因子过氧化物酶体增殖物激活受体γ（PPARγ）和CCAAT/增强子结合蛋白（C/EBPα）的mRNA表达。对已知的PPARγ上游调控因子的研究表明，疏螺旋体素下调C/EBPδ mRNA的表达，但不影响C/EBPβ的表达。在分化的早期阶段，疏螺旋体素增加分化的负调节因子如GATA结合蛋白（加塔）3、Krüppel样因子（KLF）3和KLF 7以及正调节因子KLF 4、KLF 6和KLF 15的mRNA表达。为了阐明疏螺旋体素分化抑制活性的主要介质，进行小干扰RNA（siRNA）转染实验。KLF 3和KLF 7 siRNA处理对Borreidin下调的PPARγ mRNA表达无明显影响。相比之下，在加塔-3 siRNA处理的细胞中，PPARγ的表达与对照siRNA处理的细胞没有显著差异。疏螺旋体素显著抑制对照siRNA处理的细胞中的脂质积累，并且用加塔-3 siRNA处理略微降低疏螺旋体素的抑制作用。这些结果表明疏螺旋体素部分地通过加塔-3抑制脂肪细胞分化。
An inhibitor of 3T3-L1 adipocyte differentiation was isolated from Streptomyces sp. TK08330 and identified by spectroscopy as the 18-membered macrolide borrelidin. Treatment with 1.0 μM borrelidin suppressed intracellular lipid accumulation by 80% and inhibited the expression of adipocyte-specific genes. Borrelidin suppressed the mRNA expression of two master regulators of adipocyte differentiation, peroxisome proliferator-activated receptor gamma (PPARγ) and CCAAT/enhancer binding protein (C/EBPα). Studies on well-known upstream regulators of PPARγ revealed that borrelidin down-regulated C/EBPδ mRNA expression but did not affect expression of C/EBPβ. Borrelidin increased mRNA expression of negative regulators of differentiation such as GATA-binding protein (GATA) 3, Krüppel-like factor (KLF) 3 and KLF7, as well as positive regulators, KLF4, KLF6 and KLF15, at early stages of differentiation. To elucidate a primary mediator of borrelidin differentiation inhibitory activity, small interfering RNA (siRNA) transfection experiments were performed. The mRNA expression of PPARγ, which was down-regulated by borrelidin, was not changed by KLF3 and KLF7 siRNA treatment. In contrast, expression of PPARγ in GATA-3 siRNA-treated cells was not significantly different from that of control siRNA-treated cells. Borrelidin significantly inhibited lipid accumulation in control siRNA-treated cells, and treatment with GATA-3 siRNA slightly reduced the inhibitory effect of borrelidin. These results indicate that borrelidin inhibited adipocyte differentiation partially via GATA-3.