Low-level perfluorooctanoic acid enhances 3 T3-L1 preadipocyte differentiation via altering peroxisome proliferator activated receptor gamma expression and its promoter DNA methylation
Low-level perfluorooctanoic acid enhances 3 T3-L1 preadipocyte differentiation via altering peroxisome proliferator activated receptor gamma expression and its promoter DNA methylation
复制标题
低水平全氟辛酸通过改变过氧化物酶体增殖物激活受体γ表达及其启动子DNA甲基化增强3T3-L1前脂肪细胞分化
DOI：
10.1002/jat.3549
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发表时间：
2018
期刊：
影响因子：
--
通讯作者：
Yanjian Wan
中科院分区：
文献类型：
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作者：
Yue Ma;Jie Yang;Yanjian Wan
最近的研究表明，全氟辛酸(PFOA)在肥胖的发生发展中起着一定的作用；然而，相关的机制还不清楚。我们研究了全氟辛酸暴露如何影响3个T3-L1前脂肪细胞的分化，以及相关的转录和表观遗传机制。用不同剂量的全氟辛酸(0.0 1~10 0μg m l-1)处理细胞，检测细胞的增殖、分化和甘油三酯的积累。检测PPARγ及其靶基因的表达水平。同时检测PPARγ启动子的甲基化水平和全球甲基化水平。我们发现，在全氟辛酸暴露后，脂肪细胞的增殖和分化具有浓度依赖性的促进作用。全氟辛酸还能显著增加脂质和甘油三酯的积累，且呈浓度依赖关系。PPARγ、CCAAT/增强子结合蛋白α、脂肪酸结合蛋白2和脂蛋白脂肪酶基因表达也明显增强。已知的PPARγ拮抗剂GW9662可阻断全氟辛酸诱导脂肪生成的能力。此外，在全氟辛酸作用下，PPARγ启动子上的胞嘧啶-磷酸-鸟嘌呤部位发生了显著的去甲基化。此外，全氟辛酸暴露导致全球DNA甲基化水平下降，DNA甲基转移酶基因表达水平上升。我们发现低水平的全氟辛酸处理可以诱导前脂肪细胞向成脂细胞分化，其机制可能与激活PPARγ转录和PPARγ启动子去甲基化有关。
Recent studies suggest that perfluorooctanoic acid (PFOA) can play a role in the development of obesity; however, the associated mechanisms are poorly understood. We investigated how PFOA exposure affected the differentiation of 3 T3‐L1 preadipocytes and the associated transcriptional and epigenetic mechanisms. Cells treated with different doses of PFOA (ranging from 0.01 to 100 μg ml–1) were assessed for proliferation, differentiation and triglyceride accumulation. The gene expression levels of peroxisome proliferator activated receptor gamma (PPARγ) and its target genes were measured. DNA methylation levels of PPARγ promoter and global DNA methylation levels were also tested. We found a concentration‐dependent enhancement of adipocyte prolif- eration and differentiation following PFOA exposure. PFOA also induced a significant concentra- tion‐dependent increase in the accumulation of lipid and triglyceride. Increased gene expression was also observed for PPARγ, CCAAT/enhancer binding proteins α, fatty acid binding protein 2 and lipoprotein lipase in differentiated cells after PFOA exposure. The ability of PFOA to induce adipogenesis was blocked by GW9662, a known PPARγ antagonist. In addition, significant demethylation of the cytosine–phosphate–guanine sites in the PPARγ promoter was observed after exposure to PFOA. In addition, PFOA exposure resulted in decreased global DNA methyla- tion and increased expression levels of DNA methyltransferases genes. We found that treatment with low levels of PFOA can induce adipogenic differentiation in preadipocytes, and the underly- ing mechanisms probably involve the activation of PPARγ transcription and demethylation of PPARγ promoter.