Advanced Innovation Center for Food Nutrition and Human Health, China Agricultural University, Beijing 100094, China.
Department of Animal Sciences, Washington State University, Pullman, WA 99164, USA.
J Mol Cell Biol. 2017 Aug 1;9(4):338-349. doi: 10.1093/jmcb/mjx026.
Retinoic acid (RA), a bioactive metabolite of vitamin A, is a critical mediator of cell differentiation. RA blocks adipogenesis, but mechanisms remain to be established. ZFP423 is a key transcription factor maintaining white adipose identity. We found that RA inhibits Zfp423 expression and adipogenesis via blocking DNA demethylation in the promoter of Zfp423, a process mediated by growth arrest and DNA-damage-inducible protein alpha (GADD45A). RA induces the partnering between retinoic acid receptor (RAR) and tumor suppressor inhibitor of growth protein 1 (ING1), which prevents the formation of GADD45A and ING1 complex necessary for locus-specific Zfp423 DNA demethylation. In vivo, vitamin A supplementation prevents obesity, downregulates Gadd45a expression, and reduces GADD45A binding and DNA demethylation in the Zfp423 promoter. Inhibition of Zfp423 expression due to RA contributes to the enhanced brown adipogenesis. In summary, RA inhibits white adipogenesis by inducing RAR and ING1 interaction and inhibiting Gadd45a expression, which prevents GADD45A-mediated DNA demethylation.
视黄酸（RA）是维生素 A 的生物活性代谢物，是细胞分化的关键介质。RA 阻止脂肪生成，但机制仍需建立。ZFP423 是维持白色脂肪身份的关键转录因子。我们发现 RA 通过阻断 Zfp423 启动子中的 DNA 去甲基化来抑制 Zfp423 表达和脂肪生成，这一过程由生长停滞和 DNA 损伤诱导蛋白α（GADD45A）介导。RA 诱导视黄酸受体（RAR）和生长抑制蛋白抑制剂 1（ING1）之间的伙伴关系，这阻止了形成 GADD45A 和 ING1 复合物所必需的，该复合物对于 Zfp423 基因座特异性 DNA 去甲基化是必要的。在体内，维生素 A 补充可预防肥胖，下调 Gadd45a 表达，并减少 Zfp423 启动子中的 GADD45A 结合和 DNA 去甲基化。由于 RA 导致 Zfp423 表达抑制有助于增强棕色脂肪生成。总之，RA 通过诱导 RAR 和 ING1 相互作用并抑制 Gadd45a 表达来抑制白色脂肪生成，从而阻止 GADD45A 介导的 DNA 去甲基化。
