Kang Inhae, Okla Meshail, Chung Soonkyu
Department of Food Science and Human Nutrition, University of Florida, Gainesville, FL, 32611; Department of Nutrition and Health Sciences, University of Nebraska-Lincoln, Lincoln, NE, 68583.
Department of Food Science and Human Nutrition, University of Florida, Gainesville, FL, 32611; Department of Nutrition and Health Sciences, University of Nebraska-Lincoln, Lincoln, NE, 68583.
J Nutr Biochem. 2014 Sep;25(9):946-53. doi: 10.1016/j.jnutbio.2014.04.008. Epub 2014 May 10.
Chromatin remodeling is a key mechanism in adipocyte differentiation. However, it is unknown whether dietary polyphenols are epigenetic effectors for adiposity control. Ellagic acid (EA) is a naturally occurring polyphenol in numerous fruits and vegetables. Recently, EA-containing foods have been reported to reduce adiposity. In the present study, we sought to determine whether EA inhibits adipogenesis by modifying chromatin remodeling in human adipogenic stem cells (hASCs). qPCR microarray of chromatin modification enzymes revealed that 10 μmol/L of EA significantly inhibits histone deacetylase (HDAC)9 down-regulation. In addition, EA was associated with up-regulation of HDAC activity and a marked reduction of histone acetylation levels. However, chemical inhibition of HDAC activity or depletion of HDAC9 by siRNA were not sufficient to reverse the antiadipogenic effects of EA. Intriguingly, EA treatment was also associated with reduced histone 3 arginine 17 methylation levels (H3R17me2), implying the inhibitory role of EA in coactivator-associated arginine methyltransferase 1 (CARM)1 activity during adipogenesis. Boosting CARM1 activity by delivering cell-penetrating peptides of CARM1 not only recovered H3R17me2 but also restored adipogenesis evidenced by H3 acetylation at lysine 9, HDAC9 down-regulation, PPARγ expression and triglyceride accumulation. Taken together, our data suggest that reduced CARM1 activity by EA results in a decrease of H3R17me2 levels, which may interrupt consecutive histone remodeling steps for adipocyte differentiation including histone acetylation and HDAC9 dissociation from chromatin. Our work provides the mechanistic insights into how EA, a polyphenol ubiquitously found in fruits and vegetables, attenuates human adipocyte differentiation by altering chromatin remodeling.
染色质重塑是脂肪细胞分化的关键机制。然而，膳食多酚是否为控制肥胖的表观遗传效应因子尚不清楚。鞣花酸（EA）是众多水果和蔬菜中天然存在的一种多酚。最近，据报道含EA的食物可减少肥胖。在本研究中，我们试图确定EA是否通过改变人脂肪生成干细胞（hASCs）中的染色质重塑来抑制脂肪生成。染色质修饰酶的qPCR微阵列显示，10 μmol/L的EA可显著抑制组蛋白去乙酰化酶（HDAC）9的下调。此外，EA与HDAC活性上调以及组蛋白乙酰化水平显著降低有关。然而，HDAC活性的化学抑制或通过siRNA耗尽HDAC9不足以逆转EA的抗脂肪生成作用。有趣的是，EA处理还与组蛋白3精氨酸17甲基化水平（H3R17me2）降低有关，这意味着EA在脂肪生成过程中对共激活因子相关精氨酸甲基转移酶1（CARM）1活性具有抑制作用。通过递送CARM1的细胞穿透肽来增强CARM1活性，不仅恢复了H3R17me2，还恢复了脂肪生成，这可通过赖氨酸9处的H3乙酰化、HDAC9下调、PPARγ表达和甘油三酯积累来证明。综上所述，我们的数据表明，EA导致的CARM1活性降低导致H3R17me2水平下降，这可能会中断脂肪细胞分化过程中连续的组蛋白重塑步骤，包括组蛋白乙酰化和HDAC9从染色质上解离。我们的工作为水果和蔬菜中普遍存在的多酚EA如何通过改变染色质重塑来减弱人脂肪细胞分化提供了机制性见解。
