Activation of Liver FGF21 in hepatocarcinogenesis and during hepatic stress
详细信息 查看全文
- 作者：Chaofeng Yang (1)
Weiqin Lu (3)
Tao Lin (1)
Pan You (1)
Min Ye (1)
Yanqing Huang (1)
Xianhan Jiang (1)
Cong Wang (1)
Fen Wang (1)
Mong-Hong Lee (4)
Sai-Ching J Yeung (5) (6)
Randy L Johnson (7)
Chongjuan Wei (8)
Robert Y Tsai (1)
Marsha L Frazier (8)
Wallace L McKeehan (1) (2)
Yongde Luo (1) (2) - 关键词：Adipose tissue ; Biomarker ; Endocrine FGF ; Fibroblast growth factor 21 (FGF21) ; Hepatic expression ; Hepatocellular carcinoma ; Hepatocytes ; Liver disease ; Metabolism
- 刊名：BMC Gastroenterology
- 出版年：2013
- 出版时间：December 2013
- 年：2013
- 卷：13
- 期：1
- 全文大小：1325KB
- 参考文献：1. Beenken A, Mohammadi M: The FGF family: biology, pathophysiology and therapy. / Nat Rev Drug Discov 2009, 8:235鈥?53. CrossRef
2. Inagaki T, Dutchak P, Zhao G, Ding X, Gautron L, Parameswara V, Li Y, Goetz R, Mohammadi M, Esser V, Elmquist JK, Gerard RD, Burgess SC, Hammer RE, Mangelsdorf DJ, Kliewer SA: Endocrine regulation of the fasting response by PPARalpha-mediated induction of fibroblast growth factor 21. / Cell Metab 2007, 5:415鈥?25. CrossRef
3. Kharitonenkov A, Shiyanova TL, Koester A, Ford AM, Micanovic R, Galbreath EJ, Sandusky GE, Hammond LJ, Moyers JS, Owens RA, Gromada J, Brozinick JT, Hawkins ED, Wroblewski VJ, Li DS, Mehrbod F, Jaskunas SR, Shanafelt AB: FGF-21 as a novel metabolic regulator. / J Clin Invest 2005, 115:1627鈥?635. CrossRef
4. Chen W, Hoo RL, Konishi M, Itoh N, Lee PC, Ye HY, Lam KS, Xu A: Growth hormone induces hepatic production of fibroblast growth factor 21 through a mechanism dependent on lipolysis in adipocytes. / J Biol Chem 2011, 286:34559鈥?4566. CrossRef
5. Foltz IN, Hu S, King C, Wu X, Yang C, Wang W, Weiszmann J, Stevens J, Chen JS, Nuanmanee N, Gupte J, Komorowski R, Sekirov L, Hager T, Arora T, Ge H, Baribault H, Wang F, Sheng J, Karow M, Wang M, Luo Y, McKeehan WL, Wang Z, Veniant MM, Li Y: Treating Diabetes and Obesity with an FGF21-Mimetic Antibody Activating the betaKlotho/FGFR1c Receptor Complex. / Sci Transl Med 2012, 4:162ra153. CrossRef
6. Kurosu H, Choi M, Ogawa Y, Dickson AS, Goetz R, Eliseenkova AV, Mohammadi M, Rosenblatt KP, Kliewer SA, Kuro-o M: Tissue-specific expression of betaKlotho and fibroblast growth factor (FGF) receptor isoforms determines metabolic activity of FGF19 and FGF21. / J Biol Chem 2007, 282:26687鈥?6695. CrossRef
7. Veniant MM, Hale C, Helmering J, Chen MM, Stanislaus S, Busby J, Vonderfecht S, Xu J, Lloyd DJ: FGF21 promotes metabolic homeostasis via white adipose and leptin in mice. / PLoS One 2012, 7:e40164. CrossRef
8. Yang C, Jin C, Li X, Wang F, McKeehan WL, Luo Y: Differential Specificity of Endocrine FGF19 and FGF21 to FGFR1 and FGFR4 in Complex with KLB. / PLoS One 2012, 7:e33870. CrossRef
9. Yang C, Wang C, Ye M, Jin C, He W, Wang F, McKeehan WL, Luo Y: Control of lipid metabolism by adipocyte FGFR1-mediated adipohepatic communication during hepatic stress. / Nutr Metab (Lond) 2012, 9:94. CrossRef
10. Adams AC, Chaofeng Y, Tamer C, Cheng CC, Gimeno RE, Yongde L, Alexei K: The breadth of FGF21鈥檚 metabolic actions are governed by FGFR1 in adipose tissue. / Molecular Metabolism 2012. http://download.journals.elsevierhealth.com/pdfs/journals/2212-8778/PIIS2212877812000166.pdf
11. Berglund ED, Li CY, Bina HA, Lynes SE, Michael MD, Shanafelt AB, Kharitonenkov A, Wasserman DH: Fibroblast growth factor 21 controls glycemia via regulation of hepatic glucose flux and insulin sensitivity. / Endocrinology 2009, 150:4084鈥?093. CrossRef
12. Coskun T, Bina HA, Schneider MA, Dunbar JD, Hu CC, Chen Y, Moller DE, Kharitonenkov A: Fibroblast growth factor 21 corrects obesity in mice. / Endocrinology 2008, 149:6018鈥?027. CrossRef
13. Kharitonenkov A, Wroblewski VJ, Koester A, Chen YF, Clutinger CK, Tigno XT, Hansen BC, Shanafelt AB, Etgen GJ: The metabolic state of diabetic monkeys is regulated by fibroblast growth factor-21. / Endocrinology 2007, 148:774鈥?81. CrossRef
14. Hotta Y, Nakamura H, Konishi M, Murata Y, Takagi H, Matsumura S, Inoue K, Fushiki T, Itoh N: Fibroblast growth factor 21 regulates lipolysis in white adipose tissue but is not required for ketogenesis and triglyceride clearance in liver. / Endocrinology 2009, 150:4625鈥?633. CrossRef
15. Kurosu H, Kuro OM: The Klotho gene family as a regulator of endocrine fibroblast growth factors. / Mol Cell Endocrinol 2009, 299:72鈥?8. CrossRef
16. Badman MK, Pissios P, Kennedy AR, Koukos G, Flier JS, Maratos-Flier E: Hepatic fibroblast growth factor 21 is regulated by PPARalpha and is a key mediator of hepatic lipid metabolism in ketotic states. / Cell Metab 2007, 5:426鈥?37. CrossRef
17. Estall JL, Ruas JL, Choi CS, Laznik D, Badman M, Maratos-Flier E, Shulman GI, Spiegelman BM: PGC-1alpha negatively regulates hepatic FGF21 expression by modulating the heme/Rev-Erb(alpha) axis. / Proc Natl Acad Sci USA 2009, 106:22510鈥?2515. CrossRef
18. Fisher FM, Chui PC, Antonellis PJ, Bina HA, Kharitonenkov A, Flier JS, Maratos-Flier E: Obesity is a fibroblast growth factor 21 (FGF21)-resistant state. / Diabetes 2010, 59:2781鈥?789. CrossRef
19. Lundasen T, Hunt MC, Nilsson LM, Sanyal S, Angelin B, Alexson SE, Rudling M: PPARalpha is a key regulator of hepatic FGF21. / Biochem Biophys Res Commun 2007, 360:437鈥?40. CrossRef
20. Mai K, Andres J, Biedasek K, Weicht J, Bobbert T, Sabath M, Meinus S, Reinecke F, Mohlig M, Weickert MO, Clemenz M, Pfeiffer AF, Kintscher U, Spuler S, Spranger J: Free fatty acids link metabolism and regulation of the insulin-sensitizing fibroblast growth factor-21. / Diabetes 2009, 58:1532鈥?538. CrossRef
21. Zhang X, Yeung DC, Karpisek M, Stejskal D, Zhou ZG, Liu F, Wong RL, Chow WS, Tso AW, Lam KS, Xu A: Serum FGF21 levels are increased in obesity and are independently associated with the metabolic syndrome in humans. / Diabetes 2008, 57:1246鈥?253. CrossRef
22. Oishi K, Konishi M, Murata Y, Itoh N: Time-imposed daily restricted feeding induces rhythmic expression of Fgf21 in white adipose tissue of mice. / Biochem Biophys Res Commun 2011, 412:396鈥?00. CrossRef
23. Oishi K, Tomita T: Thiazolidinediones are potent inducers of fibroblast growth factor 21 expression in the liver. / Biol Pharm Bull 2011, 34:1120鈥?121. CrossRef
24. Dushay J, Chui PC, Gopalakrishnan GS, Varela-Rey M, Crawley M, Fisher FM, Badman MK, Martinez-Chantar ML, Maratos-Flier E: Increased fibroblast growth factor 21 in obesity and nonalcoholic fatty liver disease. / Gastroenterology 2010, 139:456鈥?63. CrossRef
25. Gaemers IC, Stallen JM, Kunne C, Wallner C, van Werven J, Nederveen A, Lamers WH: Lipotoxicity and steatohepatitis in an overfed mouse model for non-alcoholic fatty liver disease. / Biochim Biophys Acta 1812, 2011:447鈥?58.
26. Li X, Fan X, Ren F, Zhang Y, Shen C, Ren G, Sun J, Zhang N, Wang W, Ning G, Yang J: Serum FGF21 levels are increased in newly diagnosed type 2 diabetes with nonalcoholic fatty liver disease and associated with hsCRP levels independently. / Diabetes Res Clin Pract 2011, 93:10鈥?6. CrossRef
27. Domingo P, Gallego-Escuredo JM, Domingo JC, Gutierrez Mdel M, Mateo MG, Fernandez I, Vidal F, Giralt M, Villarroya F: Serum FGF21 levels are elevated in association with lipodystrophy, insulin resistance and biomarkers of liver injury in HIV-1-infected patients. / AIDS 2010, 24:2629鈥?637. CrossRef
28. Kosola S, Lampela H, Gylling H, Jalanko H, Nissinen MJ, Lauronen J, Makisalo H, Vaaralahti K, Miettinen TA, Raivio T, Pakarinen MP: Cholesterol Metabolism Altered and FGF21 Levels High After Pediatric Liver Transplantation Despite Normal Serum Lipids. / Am J Transplant Epub ahead of print
29. Haeusler RA, Han S, Accili D: Hepatic FoxO1 ablation exacerbates lipid abnormalities during hyperglycemia. / J Biol Chem 2010, 285:26861鈥?6868. CrossRef
30. Oka S, Yoshihara E, Bizen-Abe A, Liu W, Watanabe M, Yodoi J, Masutani H: Thioredoxin binding protein-2/thioredoxin-interacting protein is a critical regulator of insulin secretion and peroxisome proliferator-activated receptor function. / Endocrinology 2009, 150:1225鈥?234. CrossRef
31. Teillon S, Calderon GA, Rios M: Diminished diet-induced hyperglycemia and dyslipidemia and enhanced expression of PPARalpha and FGF21 in mice with hepatic ablation of brain-derived neurotropic factor. / J Endocrinol 2011, 205:37鈥?7. CrossRef
32. Zhang YK, Yeager RL, Tanaka Y, Klaassen CD: Enhanced expression of Nrf2 in mice attenuates the fatty liver produced by a methionine- and choline-deficient diet. / Toxicol Appl Pharmacol 2010, 245:326鈥?34. CrossRef
33. Liu TF, Tang JJ, Li PS, Shen Y, Li JG, Miao HH, Li BL, Song BL: Ablation of gp78 in Liver Improves Hyperlipidemia and Insulin Resistance by Inhibiting SREBP to Decrease Lipid Biosynthesis. / Cell Metab Epub ahead of print
34. Kim KH, Jeong YT, Oh H, Kim SH, Cho JM, Kim YN, Kim SS, Kim Do H, Hur KY, Kim HK, Ko T, Han J, Kim HL, Kim J, Back SH, Komatsu M, Chen H, Chan DC, Konishi M, Itoh N, Choi CS, Lee MS: Autophagy deficiency leads to protection from obesity and insulin resistance by inducing Fgf21 as a mitokine. / Nat Med 2013, 19:83鈥?2. CrossRef
35. Schaap FG, Kremer AE, Lamers WH, Jansen PL, Gaemers IC: Fibroblast growth factor 21 is induced by endoplasmic reticulum stress. / Biochimie 2013, 95:692鈥?99. CrossRef
36. Suomalainen A, Elo JM, Pietilainen KH, Hakonen AH, Sevastianova K, Korpela M, Isohanni P, Marjavaara SK, Tyni T, Kiuru-Enari S, Pihko H, Darin N, Ounap K, Kluijtmans LA, Paetau A, Buzkova J, Bindoff LA, Annunen-Rasila J, Uusimaa J, Rissanen A, Yki-Jarvinen H, Hirano M, Tulinius M, Smeitink J, Tyynismaa H: FGF-21 as a biomarker for muscle-manifesting mitochondrial respiratory chain deficiencies: a diagnostic study. / Lancet Neurol 2011, 10:806鈥?18. CrossRef
37. Tyynismaa H, Carroll CJ, Raimundo N, Ahola-Erkkila S, Wenz T, Ruhanen H, Guse K, Hemminki A, Peltola-Mjosund KE, Tulkki V, Oresic M, Moraes CT, Pietilainen K, Hovatta I, Suomalainen A: Mitochondrial myopathy induces a starvation-like response. / Hum Mol Genet 2010, 19:3948鈥?958. CrossRef
38. Hondares E, Iglesias R, Giralt A, Gonzalez FJ, Giralt M, Mampel T, Villarroya F: Thermogenic activation induces FGF21 expression and release in brown adipose tissue. / J Biol Chem 2011, 286:12983鈥?2990. CrossRef
39. Muise ES, Azzolina B, Kuo DW, El-Sherbeini M, Tan Y, Yuan X, Mu J, Thompson JR, Berger JP, Wong KK: Adipose fibroblast growth factor 21 is up-regulated by peroxisome proliferator-activated receptor gamma and altered metabolic states. / Mol Pharmacol 2008, 74:403鈥?12. CrossRef
40. Izumiya Y, Bina HA, Ouchi N, Akasaki Y, Kharitonenkov A, Walsh K: FGF21 is an Akt-regulated myokine. / FEBS Lett 2008, 582:3805鈥?810. CrossRef
41. Huang X, Yang C, Jin C, Luo Y, Wang F, McKeehan WL: Resident hepatocyte fibroblast growth factor receptor 4 limits hepatocarcinogenesis. / Mol Carcinog 2009, 48:553鈥?62. CrossRef
42. Wei C, Amos CI, Stephens LC, Campos I, Deng JM, Behringer RR, Rashid A, Frazier ML: Mutation of Lkb1 and p53 genes exert a cooperative effect on tumorigenesis. / Cancer Res 2005, 65:11297鈥?1303. CrossRef
43. Lu L, Li Y, Kim SM, Bossuyt W, Liu P, Qiu Q, Wang Y, Halder G, Finegold MJ, Lee JS, Johnson RL: Hippo signaling is a potent in vivo growth and tumor suppressor pathway in the mammalian liver. / Proc Natl Acad Sci USA 2010, 107:1437鈥?442. CrossRef
44. Luo Y, Yang C, Lu W, Xie R, Jin C, Huang P, Wang F, McKeehan WL: Metabolic regulator betaKlotho interacts with fibroblast growth factor receptor 4 (FGFR4) to induce apoptosis and inhibit tumor cell proliferation. / J Biol Chem 2010, 285:30069鈥?0078. CrossRef
45. Uebanso T, Taketani Y, Yamamoto H, Amo K, Ominami H, Arai H, Takei Y, Masuda M, Tanimura A, Harada N, Yamanaka-Okumura H, Takeda E: Paradoxical regulation of human FGF21 by both fasting and feeding signals: is FGF21 a nutritional adaptation factor? / PLoS One 2011, 6:e22976. CrossRef
46. Nakau M, Miyoshi H, Seldin MF, Imamura M, Oshima M, Taketo MM: Hepatocellular carcinoma caused by loss of heterozygosity in Lkb1 gene knockout mice. / Cancer Res 2002, 62:4549鈥?553.
47. Panasyuk G, Espeillac C, Chauvin C, Pradelli LA, Horie Y, Suzuki A, Annicotte JS, Fajas L, Foretz M, Verdeguer F, Pontoglio M, Ferre P, Scoazec JY, Birnbaum MJ, Ricci JE, Pende M: PPARgamma contributes to PKM2 and HK2 expression in fatty liver. / Nat Commun 2012, 3:672. CrossRef
48. Yu C, Wang F, Kan M, Jin C, Jones RB, Weinstein M, Deng CX, McKeehan WL: Elevated cholesterol metabolism and bile acid synthesis in mice lacking membrane tyrosine kinase receptor FGFR4. / J Biol Chem 2000, 275:15482鈥?5489. CrossRef
49. Fon Tacer K, Bookout AL, Ding X, Kurosu H, John GB, Wang L, Goetz R, Mohammadi M, Kuro-o M, Mangelsdorf DJ, Kliewer SA: Research resource: Comprehensive expression atlas of the fibroblast growth factor system in adult mouse. / Mol Endocrinol 2010, 24:2050鈥?064. CrossRef
50. Galman C, Lundasen T, Kharitonenkov A, Bina HA, Eriksson M, Hafstrom I, Dahlin M, Amark P, Angelin B, Rudling M: The circulating metabolic regulator FGF21 is induced by prolonged fasting and PPARalpha activation in man. / Cell Metab 2008, 8:169鈥?74. CrossRef
51. Inagaki T, Choi M, Moschetta A, Peng L, Cummins CL, McDonald JG, Luo G, Jones SA, Goodwin B, Richardson JA, Gerard RD, Repa JJ, Mangelsdorf DJ, Kliewer SA: Fibroblast growth factor 15 functions as an enterohepatic signal to regulate bile acid homeostasis. / Cell Metab 2005, 2:217鈥?25. CrossRef
52. Huang X, Yang C, Luo Y, Jin C, Wang F, McKeehan WL: FGFR4 prevents hyperlipidemia and insulin resistance but underlies high-fat diet induced fatty liver. / Diabetes 2007, 56:2501鈥?510. CrossRef
53. Barthel TK, Mathern DR, Whitfield GK, Haussler CA, Hopper HA, Hsieh JC, Slater SA, Hsieh G, Kaczmarska M, Jurutka PW, Kolek OI, Ghishan FK, Haussler MR: 1,25-Dihydroxyvitamin D3/VDR-mediated induction of FGF23 as well as transcriptional control of other bone anabolic and catabolic genes that orchestrate the regulation of phosphate and calcium mineral metabolism. / J Steroid Biochem Mol Biol 2007, 103:381鈥?88. CrossRef
54. Cyphert HA, Ge X, Kohan AB, Salati LM, Zhang Y, Hillgartner FB: Activation of the Farnesoid X Receptor Induces Hepatic Expression and Secretion of Fibroblast Growth Factor 21. / J Biol Chem 2012, 287:25123鈥?5138. CrossRef
55. Uebanso T, Taketani Y, Yamamoto H, Amo K, Tanaka S, Arai H, Takei Y, Masuda M, Yamanaka-Okumura H, Takeda E: Liver X receptor negatively regulates fibroblast growth factor 21 in the fatty liver induced by cholesterol-enriched diet. / J Nutr Biochem 2012, 23:785鈥?9055. CrossRef
56. Eferl R, Ricci R, Kenner L, Zenz R, David JP, Rath M, Wagner EF: Liver tumor development. c-Jun antagonizes the proapoptotic activity of p53. / Cell 2003, 112:181鈥?92. CrossRef
57. He G, Yu GY, Temkin V, Ogata H, Kuntzen C, Sakurai T, Sieghart W, Peck-Radosavljevic M, Leffert HL, Karin M: Hepatocyte IKKbeta/NF-kappaB inhibits tumor promotion and progression by preventing oxidative stress-driven STAT3 activation. / Cancer Cell 2010, 17:286鈥?97. CrossRef
58. Arner P, Pettersson A, Mitchell PJ, Dunbar JD, Kharitonenkov A, Ryden M: FGF21 attenuates lipolysis in human adipocytes - a possible link to improved insulin sensitivity. / FEBS Lett 2008, 582:1725鈥?730. CrossRef
59. Li X, Ge H, Weiszmann J, Hecht R, Li YS, Veniant MM, Xu J, Wu X, Lindberg R, Li Y: Inhibition of lipolysis may contribute to the acute regulation of plasma FFA and glucose by FGF21 in ob/ob mice. / FEBS Lett 2009, 583:3230鈥?234. CrossRef
60. Potthoff MJ, Inagaki T, Satapati S, Ding X, He T, Goetz R, Mohammadi M, Finck BN, Mangelsdorf DJ, Kliewer SA, Burgess SC: FGF21 induces PGC-1alpha and regulates carbohydrate and fatty acid metabolism during the adaptive starvation response. / Proc Natl Acad Sci USA 2009, 106:10853鈥?0858. CrossRef
61. Ohta H, Konishi M, Itoh N: FGF10 and FGF21 as Regulators in Adipocyte Development and Metabolism. / Endocr Metab Immune Disord Drug Targets 2011, 11:302鈥?09. CrossRef
62. Suzuki M, Uehara Y, Motomura-Matsuzaka K, Oki J, Koyama Y, Kimura M, Asada M, Komi-Kuramochi A, Oka S, Imamura T: betaKlotho is required for fibroblast growth factor (FGF) 21 signaling through FGF receptor (FGFR) 1c and FGFR3c. / Mol Endocrinol 2008, 22:1006鈥?014. CrossRef
63. Angelin B, Larsson TE, Rudling M: Circulating fibroblast growth factors as metabolic regulators鈥揳 critical appraisal. / Cell Metab 2012, 16:693鈥?05. CrossRef
64. Adams LA: Biomarkers of liver fibrosis. / J Gastroenterol Hepatol 2011, 26:802鈥?09. CrossRef
65. The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-230X/13/67/prepub - 作者单位：Chaofeng Yang (1)
Weiqin Lu (3)
Tao Lin (1)
Pan You (1)
Min Ye (1)
Yanqing Huang (1)
Xianhan Jiang (1)
Cong Wang (1)
Fen Wang (1)
Mong-Hong Lee (4)
Sai-Ching J Yeung (5) (6)
Randy L Johnson (7)
Chongjuan Wei (8)
Robert Y Tsai (1)
Marsha L Frazier (8)
Wallace L McKeehan (1) (2)
Yongde Luo (1) (2)
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
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
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
文摘
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.