Kim Jina, Lee Yu-Jin, Kim Jung Min, Lee So Young, Bae Myung-Ae, Ahn Jin Hee, Han Dong Cho, Kwon Byoung-Mog
Laboratory of Chemical Biology and Genomics, Korea Research Institute of Bioscience and Biotechnology, Daejeon, 34141, Republic of Korea.
Laboratory of Chemical Biology and Genomics, Korea Research Institute of Bioscience and Biotechnology, Daejeon, 34141, Republic of Korea; University of Science and Technology in Korea, Republic of Korea.
Int J Biochem Cell Biol. 2016 Dec;81(Pt A):57-66. doi: 10.1016/j.biocel.2016.10.018. Epub 2016 Oct 22.
PPARγ agonists induced obesity in animal models as a side effect. Microarray experiments reveal that PPARγ agonist upregulates the expression of lipin-1 and this upregulation is correlated with the activity of the agonists. Lipin-1 induced by PPARγ agonists decreased the levels of PPARγ and ERK1/2 phosphorylation through direct interaction with these proteins in 3T3-L1 cells. In PPARγ agonist-treated 3T3-L1 preadipocytes, the knockdown of lipin-1 expression by small interfering RNA inhibited the adipogenesis that was induced by PPARγ agonists. In contrast, PPARγ2 expression was increased, and lipid droplets were accumulated in lipin-1-overexpressing 3T3-L1 adipocytes. Rosiglitazone (RGZ), a strong PPARγ agonist, synergistically promoted PPARγ dephosphorylation and adipogenesis in lipin-1-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 PPARγ 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 PPARγ 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.
PPARγ激动剂在动物模型中会引发肥胖这一副作用。微阵列实验显示，PPARγ激动剂会上调lipin-1的表达，且这种上调与激动剂的活性相关。PPARγ激动剂诱导产生的lipin-1通过在3T3-L1细胞中与PPARγ和ERK1/2磷酸化蛋白直接相互作用，降低了它们的水平。在经PPARγ激动剂处理的3T3-L1前脂肪细胞中，小干扰RNA介导的lipin-1表达敲低抑制了由PPARγ激动剂诱导的脂肪生成。相反，在过表达lipin-1的3T3-L1脂肪细胞中，PPARγ2表达增加，脂滴积累。罗格列酮（RGZ），一种强效PPARγ激动剂，在过表达lipin-1的3T3-L1前脂肪细胞中协同促进PPARγ去磷酸化和脂肪生成。因此，在由强效PPARγ激动剂诱导的前脂肪细胞分化过程中，lipin-1兼具转录辅因子和磷脂酸磷酸酶（PAP）的双重功能。此外，由lipin-1产生的二酰甘油（DAG）显著上调了3T3-L1细胞的脂肪生成。因此，PPARγ激动剂诱导lipin-1可能是理解这些激动剂不良反应生物学机制的一个重要因素，并且这一信息对于开发具有更低不良反应和更高耐受性的2型糖尿病（T2DM）治疗药物可能具有重要价值。
