FAM3B (PANDER) functions as a co-activator of FOXO1 to promote gluconeogenesis in hepatocytes.

Yujing Chi,Lu Tie,Junpei Wang,Fangfang Gao,Bin Geng,Zhe Wu,Weili Yang,Jichun Yang,Weiping Zhang,Yuhong Meng,Mei Li,Di Wang

doi:10.1111/jcmm.14073

Abstract

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.

Highlights

With sequence similarity 3 (FAM3) cytokine‐like gene superfamily consists four members designated as FAM3A, FAM3B, FAM3C and FAM3D respectively.[1]
Confocal imaging analyses further confirmed that pancreatic derived factor (PANDER) protein is abundantly present in the nucleus of primary mouse hepatocytes (Figure 1C) and human HepG2 cells (Figure 1D)
These findings clearly indicated that PANDER protein is abundantly present in the nucleus of both human and mouse hepatocytes

Summary

| INTRODUCTION

With sequence similarity 3 (FAM3) cytokine‐like gene superfamily consists four members designated as FAM3A, FAM3B, FAM3C and FAM3D respectively.[1]. In humans, increased circulating PANDER levels have been reported to be associated with pancreatic β cell dysfunction, hyperglycemia and insulin resistance in various races.[17–19]. Overall, these clinical and experimental studies had established that PANDER plays important roles in the regulation of glucose and lipid metabolism.[17–20]. A non‐secretory PANDER isoform has been reported to promote invasion and metastasis of human colon cancer cells.[23] These findings had raised an important hypothesis that PANDER may modulate glucose and lipid metabolism via non‐secretory mechanism in hepatocytes. PANDER directly interacts with FOXO1 to activate it in the nucleus, enhancing gluconeogenic gene expression and promoting gluconeogenesis in hepatocytes

| MATERIALS AND METHODS

| RESULTS

Findings

| DISCUSSION