Intestinal absorption of vitamin C in humans is mediated via the sodium-dependent vitamin C transporters (hSVCT1 and hSVCT2). hSVCT1 and hSVCT2 are localized at the apical and basolateral membranes, respectively, of polarized intestinal epithelia. Studies have identified low plasma levels of vitamin C and decreased expression of hSVCT1 in patients with several inflammatory conditions including inflammatory bowel disease (IBD). Investigating the underlying mechanisms responsible for regulating hSVCT1 expression are critical for understanding vitamin C homeostasis, particularly in conditions where suboptimal vitamin C levels detrimentally affect human health. Previous research has shown that hSVCT1 expression is regulated at the transcriptional level, however, little is known about epigenetic regulatory pathways that modulate hSVCT1 expression in the intestine. In this study, we found that hSVCT1 expression and function were significantly decreased in intestinal epithelial cells by the histone deacetylase inhibitors (HDACi), valproic acid (VPA), and sodium butyrate (NaB). Further, expression of transcription factor HNF1α, which is critical for SLC23A1 promoter activity, was significantly down regulated in VPA-treated cells. Chromatin immunoprecipitation (ChIP) assays showed significantly increased enrichment of tetra-acetylated histone H3 and H4 within the SLC23A1 promoter following VPA treatment. In addition, knockdown of HDAC isoforms two, and three significantly decreased hSVCT1 functional expression. Following VPA administration to mice, functional expression of SVCT1 in the jejunum was significantly decreased. Collectively, these in vitro and in vivo studies demonstrate epigenetic regulation of SVCT1 expression in intestinal epithelia partly mediated through HDAC isoforms two and three.

人体对维生素 C 的肠道吸收是通过钠依赖性维生素 C 转运蛋白（hSVCT1 和 hSVCT2）介导的。hSVCT1 和 hSVCT2 分别位于极化肠上皮细胞的顶端和基底外侧膜。研究已经发现，在患有多种炎症性疾病（包括炎症性肠病 (IBD)）的患者中，维生素 C 的血浆水平较低，hSVCT1 的表达降低。研究负责调节 hSVCT1 表达的潜在机制对于理解维生素 C 稳态至关重要，尤其是在维生素 C 水平不佳会对人类健康产生不利影响的情况下。先前的研究表明 hSVCT1 的表达在转录水平上受到调节，然而，关于调节肠道中 hSVCT1 表达的表观遗传调控途径知之甚少。在这项研究中，我们发现组蛋白脱乙酰酶抑制剂 (HDACi)、丙戊酸 (VPA) 和丁酸钠 (NaB) 会显着降低肠上皮细胞中的 hSVCT1 表达和功能。此外，转录因子 HNF1α 的表达对SLC23A1启动子活性在 VPA 处理的细胞中显着下调。染色质免疫沉淀 (ChIP) 测定显示，在VPA 处理后， SLC23A1启动子内四乙酰化组蛋白 H3 和 H4 的富集显着增加。此外，敲低 HDAC 亚型 2 和 3 显着降低了 hSVCT1 功能表达。对小鼠施用 VPA 后，空肠中 SVCT1 的功能性表达显着降低。总的来说，这些体外和体内研究表明，肠上皮细胞中 SVCT1 表达的表观遗传调控部分通过 HDAC 亚型 2 和 3 介导。