title: Pancreatic-derived factor promotes lipogenesis in the mouse liver: role of the Forkhead box 1 signaling pathway.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Physiology and Pathophysiology, Beijing, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.forename: Yujing
authors.initials: Y
authors.lastname: Chi
authors.forename: Chunjiong
authors.initials: C
authors.lastname: Wang
authors.forename: Jing
authors.initials: J
authors.lastname: Wu
authors.forename: Hang
authors.initials: H
authors.lastname: Yang
authors.forename: Dongjuan
authors.initials: D
authors.lastname: Zhang
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhu
authors.forename: Nanping
authors.initials: N
authors.lastname: Wang
authors.forename: Jichun
authors.initials: J
authors.lastname: Yang
authors.forename: Youfei
authors.initials: Y
authors.lastname: Guan
mesh_terms: D000328:Adult; D000818:Animals; D001706:Biopsy; D002478:Cells, Cultured; D016207:Cytokines / Q000235:genetics / Q000502:physiology*; D003920:Diabetes Mellitus / Q000378:metabolism / Q000503:physiopathology*; D004195:Disease Models, Animal; D005234:Fatty Liver / Q000378:metabolism / Q000503:physiopathology*; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000502:physiology*; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007333:Insulin Resistance / Q000502:physiology; D050155:Lipogenesis / Q000502:physiology*; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008875:Middle Aged; D065626:Non-alcoholic Fatty Liver Disease; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D016207:Cytokines; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; C504749:PANDER protein, mouse; D051057:Proto-Oncogene Proteins c-akt