Department of Pharmacology and Toxicology, Medical College of Georgia at Augusta University, Augusta, Georgia 30912; Vascular Biology Center, Medical College of Georgia at Augusta University, Augusta, Georgia 30912.
Vascular Biology Center, Medical College of Georgia at Augusta University, Augusta, Georgia 30912.
J Biol Chem. 2019 May 24;294(21):8577-8591. doi: 10.1074/jbc.RA118.006871. Epub 2019 Apr 10.
Enhancer of zeste homolog 2 (EZH2), an epigenetic regulator that plays a key role in cell differentiation and oncogenesis, was reported to promote adipogenic differentiation by catalyzing trimethylation of histone 3 lysine 27. However, inhibition of EZH2 induced lipid accumulation in certain cancer and hepatocyte cell lines. To address this discrepancy, we investigated the role of EZH2 in adipogenic differentiation and lipid metabolism using primary human and mouse preadipocytes and adipose-specific EZH2 knockout (KO) mice. We found that the EZH2-selective inhibitor GSK126 induced lipid accumulation in human adipocytes, without altering adipocyte differentiation marker gene expression. Moreover, adipocyte-specific EZH2 KO mice, generated by crossing EZH2 floxed mice with adiponectin-Cre mice, displayed significantly increased body weight, adipose tissue mass, and adipocyte cell size and reduced very low-density lipoprotein (VLDL) levels, as compared with littermate controls. These phenotypic alterations could not be explained by differences in feeding behavior, locomotor activity, metabolic energy expenditure, or adipose lipolysis. In addition, human adipocytes treated with either GSK126 or vehicle exhibited comparable rates of glucose-stimulated triglyceride accumulation and fatty acid uptake. Mechanistically, lipid accumulation induced by GSK126 in adipocytes was lipoprotein-dependent, and EZH2 inhibition or gene deletion promoted lipoprotein-dependent lipid uptake concomitant with up-regulated apolipoprotein E () gene expression. Deletion of blocked the effects of GSK126 to promote lipoprotein-dependent lipid uptake in murine adipocytes. Collectively, these results indicate that EZH2 inhibition promotes lipoprotein-dependent lipid accumulation via inducing expression in adipocytes, suggesting a novel mechanism of lipid regulation by EZH2.
增强子结合锌指蛋白 2（EZH2）是一种表观遗传调节剂，在细胞分化和肿瘤发生中发挥关键作用，据报道，它通过催化组蛋白 3 赖氨酸 27 的三甲基化来促进脂肪生成分化。然而，EZH2 的抑制作用在某些癌症和肝细胞系中诱导脂质积累。为了解决这一差异，我们使用原代人源和鼠源前体脂肪细胞以及脂肪特异性 EZH2 敲除（KO）小鼠研究了 EZH2 在脂肪生成分化和脂质代谢中的作用。我们发现，EZH2 选择性抑制剂 GSK126 诱导人脂肪细胞脂质积累，而不改变脂肪细胞分化标记基因的表达。此外，通过将 EZH2 floxed 小鼠与脂联素-Cre 小鼠杂交产生的脂肪特异性 EZH2 KO 小鼠与同窝对照相比，体重、脂肪组织质量、脂肪细胞大小显著增加，而极低密度脂蛋白（VLDL）水平降低。这些表型改变不能用摄食行为、运动活性、代谢能量消耗或脂肪脂解的差异来解释。此外，用 GSK126 或载体处理的人脂肪细胞表现出相当的葡萄糖刺激的甘油三酯积累和脂肪酸摄取率。在机制上，GSK126 在脂肪细胞中诱导的脂质积累依赖于脂蛋白，EZH2 抑制或基因缺失促进脂蛋白依赖性脂质摄取，同时上调载脂蛋白 E（）基因表达。的缺失阻断了 GSK126 促进小鼠脂肪细胞中脂蛋白依赖性脂质摄取的作用。总之，这些结果表明，EZH2 抑制通过诱导脂肪细胞中表达来促进脂蛋白依赖性脂质积累，提示 EZH2 通过诱导表达来促进脂蛋白依赖性脂质摄取，从而提示了 EZH2 调节脂质的一种新机制。
