Open AccessFAM3B (PANDER) functions as a co‐activator of FOXO1 to promote gluconeogenesis in hepatocytes
Author(s) -
Chi Yujing,
Meng Yuhong,
Wang Junpei,
Yang Weili,
Wu Zhe,
Li Mei,
Wang Di,
Gao Fangfang,
Geng Bin,
Tie Lu,
Zhang Weiping,
Yang Jichun
Publication year - 2019
Publication title -
journal of cellular and molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.44
H-Index - 130
eISSN - 1582-4934
pISSN - 1582-1838
DOI - 10.1111/jcmm.14073
Subject(s) - foxo1 , gluconeogenesis , activator (genetics) , gene silencing , gene expression , reporter gene , microbiology and biotechnology , biology , chemistry , signal transduction , endocrinology , gene , biochemistry , metabolism , protein kinase b
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.