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Open Access Highly Accessed Research article

Activation of Liver FGF21 in hepatocarcinogenesis and during hepatic stress

Chaofeng Yang1, Weiqin Lu3, Tao Lin1, Pan You1, Min Ye1, Yanqing Huang1, Xianhan Jiang1, Cong Wang1, Fen Wang1, Mong-Hong Lee4, Sai-Ching J Yeung56, Randy L Johnson7, Chongjuan Wei8, Robert Y Tsai1, Marsha L Frazier8, Wallace L McKeehan12 and Yongde Luo12*

Author Affiliations

1 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

2 IBT Proteomics and Nanotechnology Laboratory, Institute of Biosciences and Technology, Texas A&M Health Science Center, 2121 W. Holcombe Blvd., Houston, TX, 77030-3303, USA

3 Department of Molecular Pathology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, 77030, USA

4 Department of Molecular and Cellular Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, 77030, USA

5 Department of Emergency Medicine, The University of Texas M.D. Anderson Cancer Center, Houston, TX, 77030, USA

6 Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas M.D. Anderson Cancer Center, Houston, TX, 77030, USA

7 Department of Biochemistry and Molecular Biology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, 77030, USA

8 Department of Epidemiology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, 77030, USA

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BMC Gastroenterology 2013, 13:67  doi:10.1186/1471-230X-13-67

Published: 17 April 2013

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.

Conclusion

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.

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