Activation of Liver FGF21 in hepatocarcinogenesis and during hepatic stress

BMC Gastroenterology

Research Article

Xianhan Jiang¹  Chaofeng Yang¹  Tao Lin¹  Pan You¹  Min Ye¹  Fen Wang¹  Yanqing Huang¹  Robert Y Tsai¹  Cong Wang¹  Yongde Luo²  Wallace L McKeehan²  Randy L Johnson³  Sai-Ching J Yeung⁴  Marsha L Frazier⁵  Chongjuan Wei⁵  Weiqin Lu⁶  Mong-Hong Lee⁷ 

[1] Center for Cancer and Stem Cell Biology, Institute of Biosciences and Technology, Texas A&M Health Science Center, 2121 W. Holcombe Blvd, 77030-3303, Houston, TX, USA;Center for Cancer and Stem Cell Biology, Institute of Biosciences and Technology, Texas A&M Health Science Center, 2121 W. Holcombe Blvd, 77030-3303, Houston, TX, USA;IBT Proteomics and Nanotechnology Laboratory, Institute of Biosciences and Technology, Texas A&M Health Science Center, 2121 W. Holcombe Blvd, 77030-3303, Houston, TX, USA;Department of Biochemistry and Molecular Biology, The University of Texas M.D. Anderson Cancer Center, 77030, Houston, TX, USA;Department of Emergency Medicine, The University of Texas M.D. Anderson Cancer Center, 77030, Houston, TX, USA;Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas M.D. Anderson Cancer Center, 77030, Houston, TX, USA;Department of Epidemiology, The University of Texas M.D. Anderson Cancer Center, 77030, Houston, TX, USA;Department of Molecular Pathology, The University of Texas M.D. Anderson Cancer Center, 77030, Houston, TX, USA;Department of Molecular and Cellular Oncology, The University of Texas M.D. Anderson Cancer Center, 77030, Houston, TX, USA;

关键词: Adipose tissue;    Biomarker;    Endocrine FGF;    Fibroblast growth factor 21 (FGF21);    Hepatic expression;    Hepatocellular carcinoma;    Hepatocytes;    Liver disease;    Metabolism;   

DOI  :  10.1186/1471-230X-13-67

 received in 2013-01-02, accepted in 2013-04-09,  发布年份 2013

来源: Springer

【 摘 要 】

BackgroundFGF21 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.MethodsIn 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.ResultsWe 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.ConclusionFGF21 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.

【 授权许可】

Unknown   
© Yang et al.; licensee BioMed Central Ltd. 2013. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.