PPARγ agonists induce adipocyte differentiation by modulating the expression of Lipin-1, which acts as a PPARγ phosphatase
PPARγ agonists induce adipocyte differentiation by modulating the expression of Lipin-1, which acts as a PPARγ phosphatase
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DOI：
10.1016/j.biocel.2016.10.018
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发表时间：
2016-12-01
影响因子：
4
通讯作者：
Kwon, Byoung-Mog
中科院分区：
文献类型：
--
作者：
Kim, Jina;Lee, Yu-Jin;Kwon, Byoung-Mog
在动物模型中，PPAR γ激动剂诱导肥胖作为副作用。微阵列实验表明，PPAR γ激动剂上调lipin-1的表达，这种上调与激动剂的活性相关。在3 T3-L1细胞中，由PPAR γ激动剂诱导的Lipin-1通过与这些蛋白直接相互作用降低了PPAR γ和ERK 1/2磷酸化水平。在经PPAR γ激动剂处理的3 T3-L1前脂肪细胞中，通过小干扰RNA敲低lipin-1表达抑制了由PPAR γ激动剂诱导的脂肪形成。与此相反，过氧化物酶体增殖物激活受体γ 2的表达增加，脂质滴积累在脂质-1-过表达的3 T3-L1脂肪细胞。罗格列酮（RGZ），一种强的PPAR γ激动剂，协同促进过表达lipin-1的3 T3-L1前脂肪细胞中的PPAR γ去磷酸化和脂肪生成。因此，lipin-1具有双重功能，作为转录辅因子和磷脂酸磷酸酶（PAP）的前脂肪细胞的分化诱导的强PPAR γ激动剂。此外，3 T3-L1细胞的脂肪形成被由lipin-1产生的二酰基甘油（DAG）显著上调。因此，lipin-1诱导的PPAR γ激动剂可能是一个重要的因素，在了解激动剂的不良反应的生物学机制，这一信息可能是有价值的2型糖尿病（T2 DM）治疗药物的发展，减少不良反应和更大的耐受性。(C)2016爱思唯尔有限公司版权所有。
PPAR gamma agonists induced obesity in animal models as a side effect. Microarray experiments reveal that PPAR gamma agonist upregulates the expression of lipin-1 and this upregulation is correlated with the activity of the agonists. Lipin-1 induced by PPAR gamma agonists decreased the levels of PPAR gamma and ERK1/2 phosphorylation through direct interaction with these proteins in 3T3-L1 cells. In PPAR gamma agonist-treated 3T3-L1 preadipocytes, the knockdown of lipin-1 expression by small interfering RNA inhibited the adipogenesis that was induced by PPAR gamma agonists. In contrast, PPAR gamma 2 expression was increased, and lipid droplets were accumulated in lipin-l-overexpressing 3T3-L1 adipocytes. Rosiglitazone (RGZ), a strong PPAR gamma agonist, synergistically promoted PPAR gamma dephosphorylation and adipogenesis in lipin-l-overexpressing 3T3-L1 preadipocytes. Therefore, lipin-1 has dual functions as a transcriptional cofactor and phosphatidate phosphatase (PAP) in the differentiation of preadipocyte cells induced by strong PPAR gamma agonists. In addition, the adipogenesis of 3T3-L1 cells was markedly upregulated by diacylglycerol (DAG), which was produced by lipin-1. Therefore, lipin-1 induction by PPAR gamma agonists might be an important factor in understanding the biological mechanism of the agonists' adverse effects, and this information may be valuable in the development of type-2 diabetes mellitus (T2DM) therapeutics with reduced adverse effects and greater tolerability. (C) 2016 Elsevier Ltd. All rights reserved.