title: Activation of Liver FGF21 in hepatocarcinogenesis and during hepatic stress.
abstract: BACKGROUND
  FGF21 is a promising intervention therapy for metabolic diseases as fatty liver, obesity and diabetes. Recent results suggest that FGF21 is highly expressed in hepatocytes under metabolic stress caused by starvation, hepatosteatosis, obesity and diabetes. Hepatic FGF21 elicits metabolic benefits by targeting adipocytes of the peripheral adipose tissue through the transmembrane FGFR1-KLB complex. Ablation of adipose FGFR1 resulted in increased hepatosteatosis under starvation conditions and abrogation of the anti-obesogenic action of FGF21. These results indicate that FGF21 may be a stress responsive hepatokine that targets adipocytes and adipose tissue for alleviating the damaging effects of stress on the liver. However, it is unclear whether hepatic induction of FGF21 is limited to only metabolic stress, or to a more general hepatic stress resulting from liver pathogenesis and injury.
  
  
  METHODS
  In this survey-based study, we examine the nature of hepatic FGF21 activation in liver tissues and tissue sections from several mouse liver disease models and human patients, by quantitative PCR, immunohistochemistry, protein chemistry, and reporter and CHIP assays. The liver diseases include genetic and chemical-induced HCC, liver injury and regeneration, cirrhosis, and other types of liver diseases.
  
  
  RESULTS
  We found that mouse FGF21 is induced in response to chemical (DEN treatment) and genetic-induced hepatocarcinogenesis (disruptions in LKB1, p53, MST1/2, SAV1 and PTEN). It is also induced in response to loss of liver mass due to partial hepatectomy followed by regeneration. The induction of FGF21 expression is potentially under the control of stress responsive transcription factors p53 and STAT3. Serum FGF21 levels correlate with FGF21 expression in hepatocytes. In patients with hepatitis, fatty degeneration, cirrhosis and liver tumors, FGF21 levels in hepatocytes or phenotypically normal hepatocytes are invariably elevated compared to normal health subjects.
  
  
  CONCLUSIONS
  FGF21 is an inducible hepatokine and could be a biomarker for normal hepatocyte function. Activation of its expression is a response of functional hepatocytes to a broad spectrum of pathological changes that impose both cellular and metabolic stress on the liver. Taken together with our recent data, we suggest that hepatic FGF21 is a general stress responsive factor that targets adipose tissue for normalizing local and systemic metabolic parameters while alleviating the overload and damaging effects imposed by the pathogenic stress on the liver. This study therefore provides a rationale for clinical biomarker studies in humans.
authors.affiliation: Center for Cancer and Stem Cell Biology, Institute of Biosciences and Technology, Texas A&M Health Science Center, 2121 W, Holcombe Blvd,, Houston, TX 77030-3303, USA.
authors.forename: Chaofeng
authors.initials: C
authors.lastname: Yang
authors.forename: Weiqin
authors.initials: W
authors.lastname: Lu
authors.forename: Tao
authors.initials: T
authors.lastname: Lin
authors.forename: Pan
authors.initials: P
authors.lastname: You
authors.forename: Min
authors.initials: M
authors.lastname: Ye
authors.forename: Yanqing
authors.initials: Y
authors.lastname: Huang
authors.forename: Xianhan
authors.initials: X
authors.lastname: Jiang
authors.forename: Cong
authors.initials: C
authors.lastname: Wang
authors.forename: Fen
authors.initials: F
authors.lastname: Wang
authors.forename: Mong-Hong
authors.initials: MH
authors.lastname: Lee
authors.forename: Sai-Ching J
authors.initials: SC
authors.lastname: Yeung
authors.forename: Randy L
authors.initials: RL
authors.lastname: Johnson
authors.forename: Chongjuan
authors.initials: C
authors.lastname: Wei
authors.forename: Robert Y
authors.initials: RY
authors.lastname: Tsai
authors.forename: Marsha L
authors.initials: ML
authors.lastname: Frazier
authors.forename: Wallace L
authors.initials: WL
authors.lastname: McKeehan
authors.forename: Yongde
authors.initials: Y
authors.lastname: Luo
mesh_terms: D055372:AMP-Activated Protein Kinases; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000139:chemically induced / Q000378:metabolism*; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism*; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism*; D004052:Diethylnitrosamine; D004195:Disease Models, Animal; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000378:metabolism*; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D000090265:Klotho Proteins; D008099:Liver / Q000378:metabolism / Q000473:pathology / Q000601:surgery; D008103:Liver Cirrhosis / Q000378:metabolism*; D008113:Liver Neoplasms / Q000139:chemically induced / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D051499:Receptor, Fibroblast Growth Factor, Type 4 / Q000235:genetics; D050796:STAT3 Transcription Factor / Q000378:metabolism; D013312:Stress, Physiological; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: C418622:Klb protein, mouse; D008565:Membrane Proteins; D012333:RNA, Messenger; D050796:STAT3 Transcription Factor; D016159:Tumor Suppressor Protein p53; C414620:fibroblast growth factor 21; D004052:Diethylnitrosamine; D005346:Fibroblast Growth Factors; D051499:Receptor, Fibroblast Growth Factor, Type 4; D017346:Protein Serine-Threonine Kinases; C491654:Stk11 protein, mouse; D055372:AMP-Activated Protein Kinases; D000090265:Klotho Proteins