Carnosic acid and carnosol inhibit adipocyte differentiation in mouse 3T3-L1 cells through induction of phase2 enzymes and activation of glutathione metabolism
Carnosic acid and carnosol inhibit adipocyte differentiation in mouse 3T3-L1 cells through induction of phase2 enzymes and activation of glutathione metabolism
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DOI：
10.1016/j.bbrc.2009.03.059
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发表时间：
2009-05-08
影响因子：
3.1
通讯作者：
Satoh, Takumi
中科院分区：
文献类型：
--
作者：
Takahashi, Toshiyuki;Tabuchi, Takahito;Satoh, Takumi
在以前的研究中，我们报道了源自迷迭香的鼠尾草酸（CA）和鼠尾草酚（CS）通过激活Keap 1/Nrf 2通路来保护皮层神经元，该激活是通过“亲电”醌型CA或CS对Keap 1蛋白的关键半胱氨酸巯基的S-烷基化来启动的。在此，我们发现CA和CS抑制小鼠前脂肪细胞3 T3-L1细胞向脂肪细胞的体外分化。相反，其他生理活性和迷迭香来源的化合物是完全阴性的。这些行动似乎是介导的激活抗氧化反应元件（ARE）和诱导2相酶。这一估计是合理的，我们目前的研究结果，只有CA和CS迷迭香起源的化合物显着激活ARE和诱导的第2阶段的酶。接下来，我们进行了cDNA微阵列分析以鉴定负责这些生物学作用的基因，并发现2相酶（Gsta 2、Gclc、Abcc 4和Abcc 1）构成了前5个CA诱导基因中的4个，所有这些酶都参与谷胱甘肽（GSH）的代谢。此外，CA和CS，但不是其他化合物测试，显着增加细胞内总GSH水平。因此，我们认为，GSH代谢的刺激可能是抑制脂肪细胞分化的关键步骤，并建议亲电化合物，如CA和CS可能是潜在的药物，对肥胖相关的疾病。(C)2009 Elsevier Inc. All rights reserved.
In the previous studies, we reported that carnosic acid (CA) and carnosol (CS) originating from rosemary protected cortical neurons by activating the Keap1/Nrf2 pathway, which activation was initiated by S-alkylation of the critical cysteine thiol of the Keap1 protein by the "electrophilic" quinone-type of CA or CS. Here, we found that CA and CS inhibited the in vitro differentiation of mouse preadipocytes, 3T3-L1 cells, into adipocytes. In contrast, other physiologically-active and rosemary-originated compounds were completely negative. These actions seemed to be mediated by activation of the antioxidant-response element (ARE) and induction of phase2 enzymes. This estimation is justified by our present findings that only CA and CS among rosemary-originated compounds significantly activated the ARE and induced the phase2 enzymes. Next, we performed cDNA microarray analysis in order to identify the gene(s) responsible for these biological actions and found that phase2 enzymes (Gsta2, Gclc, Abcc4, and Abcc1), all of which are involved in the metabolism Of glutathione (GSH), constituted 4 of the top 5 CA-induced genes. Furthermore, CA and CS, but not the other compounds tested, significantly increased the intracellular level of total GSH. Thus, we propose that the stimulation of GSH metabolism may be a critical step for the inhibition of adipocyte differentiation in 3T3-L1 cells and suggest that pro-electrophilic Compounds such as CA and CS may be potential drugs against obesity-related diseases. (C) 2009 Elsevier Inc. All rights reserved.