Department of Integrative Bioscience and Biotechnology, Sejong University, 209 Neungdong-ro, Gwangjin-gu, Seoul, 05006, Korea.
Korea Food Research Institute, Research Group of Healthcare, 245 Nongsaengmyeong-ro, Jeonju, Jeonbuk, 55365, Korea.
Phytother Res. 2019 Sep;33(9):2429-2439. doi: 10.1002/ptr.6434. Epub 2019 Jul 29.
Previously, we reported that piperine, one of the major pungent components in black pepper, attenuates adipogenesis by repressing PPARγ activity in 3T3-L1 preadipocytes. However, the epigenetic mechanisms underlying this activity remain unexplored. Here, gene set enrichment analysis using microarray data indicated that there was significant downregulation of adipogenesis-associated and PPARγ target genes and upregulation of genes bound with H3K27me3 in response to piperine. As shown by Gene Ontology analysis, the upregulated genes are related to lipid oxidation and polycomb repressive complex 2 (PRC2). Chromatin immunoprecipitation assays revealed that PPARγ (and its coactivators), H3K4me3, and H3K9ac were less enriched at the PPAR response element of three adipogenic genes, whereas increased accumulation of H3K9me2, H3K27me3, and Ezh2 was found, which likely led to the reduced gene expression. Further analysis using three lipolytic genes revealed the opposite enrichment pattern of H3K4me3 and H3K27me3 at the Ezh2 binding site. Treatment with GSK343, an Ezh2 inhibitor, elevated lipolytic gene expression by decreasing the enrichment of H3K27me3 during adipogenesis, which confirms that Ezh2 plays a repressive role in lipolysis. Overall, these results suggest that piperine regulates the expression of adipogenic and lipolytic genes by dynamic regulation of histone modifications, leading to the repression of adipocyte differentiation.
先前，我们曾报道黑胡椒中的主要辛辣成分之一胡椒碱可通过抑制 3T3-L1 前脂肪细胞中 PPARγ 的活性来减弱脂肪生成。然而，其作用的表观遗传机制仍未得到探索。在这里，利用微阵列数据进行基因集富集分析表明，胡椒碱可显著下调脂肪生成相关基因和 PPARγ 靶基因，并上调与 H3K27me3 结合的基因。如基因本体论分析所示，上调的基因与脂质氧化和多梳抑制复合物 2（PRC2）有关。染色质免疫沉淀分析显示，在三个脂肪生成基因的 PPAR 反应元件中，PPARγ（及其共激活因子）、H3K4me3 和 H3K9ac 的富集程度降低，而 H3K9me2、H3K27me3 和 Ezh2 的积累增加，这可能导致基因表达减少。对三种脂肪分解基因的进一步分析显示，Ezh2 结合位点的 H3K4me3 和 H3K27me3 的富集模式相反。用 Ezh2 抑制剂 GSK343 处理可通过降低脂肪生成过程中 H3K27me3 的富集来提高脂肪分解基因的表达，这证实了 Ezh2 在脂肪分解中发挥抑制作用。总的来说，这些结果表明，胡椒碱通过动态调节组蛋白修饰来调节脂肪生成和脂肪分解基因的表达，从而抑制脂肪细胞分化。
