Department of Central Laboratory & Institute of Clinical Molecular Biology, Peking University People's Hospital, Beijing, China.
Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Key Laboratory of Cardiovascular Science of the Ministry of Education, Center for Non-coding RNA Medicine, Peking University Health Science Center, Beijing, China.
J Cell Mol Med. 2019 Mar;23(3):1746-1758. doi: 10.1111/jcmm.14073. Epub 2018 Nov 28.
FAM3B, also known as PANcreatic DERived factor (PANDER), promotes gluconeogenesis and lipogenesis in hepatocytes. However, the underlying mechanism(s) still remains largely unclear. This study determined the mechanism of PANDER-induced FOXO1 activation in hepatocytes. In mouse livers and cultured hepatocytes, PANDER protein is located in both the cytoplasm and nucleus. Nuclear PANDER distribution was increased in the livers of obese mice. In cultured mouse and human hepatocytes, PANDER was co-localized with FOXO1 in the nucleus. PANDER directly interacted with FOXO1 in mouse and human hepatocytes. PANDER overexpression enhanced PANDER-FOXO1 interaction, and detained FOXO1 in the nucleus upon insulin stimulation in hepatocytes. With the increase in PANDER-FOXO1 interaction, PANDER overexpression upregulated the expression of gluconeogenic genes and promoted gluconeogenesis in both human and mouse hepatocytes. Luciferase reporter assays further revealed that PANDER augmented the transcriptional activity of FOXO1 on gluconeogenic genes. Moreover, PANDER overexpression also interfered the binding of AS1842856, a specific FOXO1 inhibitor, with FOXO1, and impaired its inhibitory effects on gluconeogenic gene expression and gluconeogenesis in hepatocytes. siRNA mediated-silencing of FOXO1 inhibited PANDER-promoted gluconeogenic gene expression and glucose production in hepatocytes. In conclusion, PANDER protein is abundantly present in the nucleus, where it functions as a new co-activator of FOXO1 to induce gluconeogenic gene expression in hepatocytes.
FAM3B，也被称为胰腺衍生因子（PANDER），在肝细胞中促进糖异生和脂肪生成。然而，其潜在机制仍很大程度上不清楚。本研究旨在确定 PANDER 诱导肝细胞 FOXO1 激活的机制。在小鼠肝脏和培养的肝细胞中，PANDER 蛋白存在于细胞质和细胞核中。肥胖小鼠肝脏中核内 PANDER 分布增加。在培养的小鼠和人肝细胞中，PANDER 与 FOXO1 共定位在细胞核中。PANDER 可在小鼠和人肝细胞中与 FOXO1 直接相互作用。PANDER 过表达增强了 PANDER-FOXO1 的相互作用，并在胰岛素刺激时将 FOXO1 滞留在肝细胞的核内。随着 PANDER-FOXO1 相互作用的增加，PANDER 过表达上调了人源和鼠源肝细胞中糖异生基因的表达，并促进了糖异生。荧光素酶报告基因实验进一步表明，PANDER 增强了 FOXO1 对糖异生基因的转录活性。此外，PANDER 过表达还干扰了 AS1842856（一种特定的 FOXO1 抑制剂）与 FOXO1 的结合，并损害了其对肝细胞中糖异生基因表达和糖异生的抑制作用。siRNA 介导的 FOXO1 沉默抑制了 PANDER 促进的肝细胞中糖异生基因表达和葡萄糖生成。总之，PANDER 蛋白在细胞核中大量存在，作为 FOXO1 的新共激活因子，在肝细胞中诱导糖异生基因表达。
