Pancreatic-derived factor promotes lipogenesis in the mouse liver: Role of the Forkhead box 1 signaling pathway

Authors

  • Jing Li,

    1. Department of Physiology and Pathophysiology, Beijing, China
    Search for more papers by this author
    • These authors contributed equally to this work.

  • Yujing Chi,

    1. Department of Physiology and Pathophysiology, Beijing, China
    Search for more papers by this author
    • Potential conflict of interest: Nothing to report.

  • Chunjiong Wang,

    1. Department of Physiology and Pathophysiology, Beijing, China
    Search for more papers by this author
  • Jing Wu,

    1. Department of Physiology and Pathophysiology, Beijing, China
    Search for more papers by this author
  • Hang Yang,

    1. Department of Physiology and Pathophysiology, Beijing, China
    Search for more papers by this author
  • Dongjuan Zhang,

    1. Department of Physiology and Pathophysiology, Beijing, China
    Search for more papers by this author
  • Yi Zhu,

    1. Department of Physiology and Pathophysiology, Beijing, China
    2. Peking (Beijing) University Diabetes Center, Beijing, China
    3. Key Laboratory of Molecular Cardiovascular Science, Peking (Beijing) University Health Science Center, Beijing, China
    Search for more papers by this author
  • Nanping Wang,

    1. Peking (Beijing) University Diabetes Center, Beijing, China
    2. Key Laboratory of Molecular Cardiovascular Science, Peking (Beijing) University Health Science Center, Beijing, China
    Search for more papers by this author
  • Jichun Yang,

    Corresponding author
    1. Department of Physiology and Pathophysiology, Beijing, China
    2. Peking (Beijing) University Diabetes Center, Beijing, China
    3. Key Laboratory of Molecular Cardiovascular Science, Peking (Beijing) University Health Science Center, Beijing, China
    • Department of Physiology and Pathophysiology, Peking (Beijing) University Health Science Center, 38 Xueyuan Road, Beijing, China 100191
    Search for more papers by this author
  • Youfei Guan

    Corresponding author
    1. Department of Physiology and Pathophysiology, Beijing, China
    2. Peking (Beijing) University Diabetes Center, Beijing, China
    3. Key Laboratory of Molecular Cardiovascular Science, Peking (Beijing) University Health Science Center, Beijing, China
    • Department of Physiology and Pathophysiology, Peking (Beijing) University Health Science Center, 38 Xueyuan Road, Beijing, China 100191
    Search for more papers by this author

  • Supported by grants from the Natural Science Foundation (30771030, 81030003, 30725033, and 30890041 to Y. G. and J. Y.) and the Ministry of Science and Technology (2010CB912503 to Y. G.). J. Y. is supported by the “New Century Excellent Talents in Universities” Program from the Ministry of Education of China.

Abstract

Pancreatic-derived factor (PANDER) is a pancreatic islet-specific cytokine that cosecretes with insulin and is important for β cell function. Here, we show that PANDER is constitutively expressed in hepatocytes, and its expression is significantly increased in steatotic livers of diabetic insulin-resistant db/db mice and mice fed a high-fat diet. Overexpression of PANDER in the livers of C57Bl/6 mice promoted lipogenesis, with increased Forkhead box 1 (FOXO1) expression, whereas small interfering RNA–mediated knockdown of hepatic PANDER significantly attenuated steatosis, with reduced FOXO1 expression in db/db mice. Hepatic PANDER silencing also attenuated insulin resistance and hyperglycemia in db/db mice. In cultured hepatocytes, PANDER overexpression induced lipid deposition, increased FOXO1 expression, and suppressed insulin-stimulated Akt activation and FOXO1 inactivation. Moreover, FOXO1 overexpression increased PANDER expression in cultured hepatocytes and mouse livers. Conclusion: PANDER promotes lipogenesis and compromises insulin signaling in the liver by increasing FOXO1 activity. PANDER may represent a potential therapeutic target for the treatment of fatty liver and insulin resistance. (HEPATOLOGY 2011;)

Ancillary