Pancreatic-derived Factor Promotes Lipogenesis in the Mouse Liver: Role of the Forkhead Box 1 Signaling Pathway

Hepatology. 2011 Jun;53(6):1906-16. doi: 10.1002/hep.24295. Epub 2011 May 2.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Animals
  • Biopsy
  • Cells, Cultured
  • Cytokines / genetics
  • Cytokines / physiology*
  • Diabetes Mellitus / metabolism
  • Diabetes Mellitus / physiopathology*
  • Disease Models, Animal
  • Fatty Liver / metabolism
  • Fatty Liver / physiopathology*
  • Forkhead Box Protein O1
  • Forkhead Transcription Factors / physiology*
  • Hepatocytes / metabolism
  • Hepatocytes / pathology
  • Humans
  • Insulin Resistance / physiology
  • Lipogenesis / physiology*
  • Liver / metabolism*
  • Liver / pathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Mutant Strains
  • Middle Aged
  • Non-alcoholic Fatty Liver Disease
  • Proto-Oncogene Proteins c-akt / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Signal Transduction / physiology*

Substances

  • Cytokines
  • Forkhead Box Protein O1
  • Forkhead Transcription Factors
  • Foxo1 protein, mouse
  • PANDER protein, mouse
  • Proto-Oncogene Proteins c-akt