title: Exendin-4 regulates lipid metabolism and fibroblast growth factor 21 in hepatic steatosis.
abstract: OBJECTIVE
  Hepatokine fibroblast growth factor (FGF) 21 takes part in the regulation of lipid metabolism in the liver and adipose tissue. We investigated whether exendin-4 regulates the expression of FGF21 in the liver, and whether the effects of exendin-4 on the regulation of FGF21 expression are mediated via silent mating type information regulation 2 homolog (SIRT) 1 or SIRT6.
  
  
  METHODS
  The C57BL/6J mice were fed a low fat diet, high fat diet, or high fat diet with 1 nmol/kg/day exendin-4 intraperitoneal injection for 10 weeks. HepG2 used in vitro study was treated with palmitic aicd (0.4 mM) with or without exendin-4 (100 nM) and FGF21 (50 nM) for 24 hours. The change of FGF21 and its receptors expression by exendin-4 were measured using quantitative real-time RT-PCR and Western blot. The intracellular lipid content in HepG2 cells was evaluated by Oil Red O staining. Inhibition of FGF21, SIRT1 and SIRT6, by 10 nM siRNA was performed to establish the signaling pathway of exendin-4 action in hepatic lipid metabolism.
  
  
  RESULTS
  Exendin-4 increased the expression of FGF21 and its receptors in high fat diet-induced obese mice. In addition, recombinant FGF21 treatment reduced lipid content in palmitic acid-treated HepG2 cells. We also observed significantly decreased expression of peroxisomal proliferator-activated receptor (PPAR) α and medium-chain acyl-coenzyme A dehydrogenase (MCAD) in hepatocytes transfected with FGF21 siRNA. In cells treated with exendin-4, inhibition of SIRT1, but not SIRT6, by siRNA significantly repressed the expression of FGF21 mRNA, whereas decreased SIRT1 expression by inhibition of FGF21 was not observed.
  
  
  CONCLUSIONS
  These data suggest that exendin-4 could improve fatty liver by increasing SIRT1-mediated FGF21.
authors.affiliation: Institute of Medical Research, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul 110-746, Republic of Korea.
authors.forename: Jinmi
authors.initials: J
authors.lastname: Lee
authors.affiliation: Institute of Medical Research, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul 110-746, Republic of Korea.
authors.forename: Seok-Woo
authors.initials: SW
authors.lastname: Hong
authors.affiliation: Department of Endocrinology and Metabolism, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul 110-746, Republic of Korea.
authors.forename: Se Eun
authors.initials: SE
authors.lastname: Park
authors.affiliation: Department of Endocrinology and Metabolism, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul 110-746, Republic of Korea.
authors.forename: Eun-Jung
authors.initials: EJ
authors.lastname: Rhee
authors.affiliation: Department of Endocrinology and Metabolism, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul 110-746, Republic of Korea.
authors.forename: Cheol-Young
authors.initials: CY
authors.lastname: Park
authors.affiliation: Department of Endocrinology and Metabolism, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul 110-746, Republic of Korea.
authors.forename: Ki-Won
authors.initials: KW
authors.lastname: Oh
authors.affiliation: Department of Endocrinology and Metabolism, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul 110-746, Republic of Korea.
authors.forename: Sung-Woo
authors.initials: SW
authors.lastname: Park
authors.affiliation: Department of Endocrinology and Metabolism, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul 110-746, Republic of Korea. Electronic address: drlwy@hanmail.net.
authors.forename: Won-Young
authors.initials: WY
authors.lastname: Lee
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D000077270:Exenatide; D005346:Fibroblast Growth Factors / Q000378:metabolism*; D006801:Humans; D050356:Lipid Metabolism / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D010455:Peptides / Q000502:physiology*; D060888:Real-Time Polymerase Chain Reaction; D056564:Sirtuin 1 / Q000378:metabolism; D014688:Venoms
chemical_list: D010455:Peptides; D014688:Venoms; C414620:fibroblast growth factor 21; D005346:Fibroblast Growth Factors; D000077270:Exenatide; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1
keywords: Exendin-4; FGF21; FGFRs; Fatty acid oxidation; SIRT1