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ISSN 2097-3497 (Online)
CN 22-1108/R
Volume 37 Issue 6
Jun.  2021
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Article Navigation >  Journal of Clinical Hepatology  > 2021  >  37(6): 1262-1267

Current status and perspectives of fibroblast growth factor 21 in nonalcoholic fatty liver disease

DOI: 10.3969/j.issn.1001-5256.2021.06.006
  • a.

    State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Hong Kong 999077, China

  • b.

    Department of Medicine, The University of Hong Kong, Hong Kong 999077, China

  • c.

    Department of Pharmacology and Pharmacy, The University of Hong Kong, Hong Kong 999077, China

  • Received Date: 2021-04-03
  • Accepted Date: 2021-04-13
  • Published Date: 2021-06-20
    Abstract
  • Fibroblast growth factor 21 (FGF21) is a peptide hormone predominantly secreted by the liver and plays a crucial role in maintaining whole-body energy metabolism and regulating insulin sensitivity. A large number of clinical studies have demonstrated that serum FGF21 levels are increased in obese patients with non-alcoholic fatty liver disease (NAFLD), and high circulating FGF21 is a sensitive biomarker for predicting the onset and progression of NAFLD. Injection of exogenous FGF21 can effectively alleviate pathological process in both animal models and NAFLD patients. This review aims to describe the molecular mechanism underlying the hepatoprotective effects of FGF21; to summarize the current data and challenges of the clinical trials on FGF21 analogs and receptor agonists in the treatment of NAFLD and nonalcoholic steatohepatitis (NASH); and to speculate the future directions of FGF21 as a diagnosis and treatment for NAFLD.

     

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    • References(44)
  • [1]
    HUI Q, JIN Z, LI X, et al. FGF family: From drug development to clinical application[J]. Int J Mol Sci, 2018, 19(7): 1875. DOI: 10.3390/ijms19071875.
    [2]
    NISHIMURA T, NAKATAKE Y, KONISHI M, et al. Identification of a novel FGF, FGF-21, preferentially expressed in the liver[J]. Biochim Biophys Acta, 2000, 1492(1): 203-206. DOI: 10.1016/s0167-4781(00)00067-1.
    [3]
    KHARITONENKOV A, SHIYANOVA TL, KOESTER A, et al. FGF-21 as a novel metabolic regulator[J]. J Clin Invest, 2005, 115(6): 1627-1635. DOI: 10.1172/JCI23606.
    [4]
    XU J, LLOYD DJ, HALE C, et al. Fibroblast growth factor 21 reverses hepatic steatosis, increases energy expenditure, and improves insulin sensitivity in diet-induced obese mice[J]. Diabetes, 2009, 58(1): 250-259. DOI: 10.2337/db08-0392.
    [5]
    KHARITONENKOV A, WROBLEWSKI VJ, KOESTER A, et al. The metabolic state of diabetic monkeys is regulated by fibroblast growth factor-21[J]. Endocrinology, 2007, 148(2): 774-781. DOI: 10.1210/en.2006-1168.
    [6]
    BADMAN MK, PISSIOS P, KENNEDY AR, et al. Hepatic fibroblast growth factor 21 is regulated by PPARalpha and is a key mediator of hepatic lipid metabolism in ketotic states[J]. Cell Metab, 2007, 5(6): 426-437. DOI: 10.1016/j.cmet.2007.05.002.
    [7]
    LIANG Q, ZHONG L, ZHANG J, et al. FGF21 maintains glucose homeostasis by mediating the cross talk between liver and brain during prolonged fasting[J]. Diabetes, 2014, 63(12): 4064-4075. DOI: 10.2337/db14-0541.
    [8]
    LIN Z, PAN X, WU F, et al. Fibroblast growth factor 21 prevents atherosclerosis by suppression of hepatic sterol regulatory element-binding protein-2 and induction of adiponectin in mice[J]. Circulation, 2015, 131(21): 1861-1871. DOI: 10.1161/CIRCULATIONAHA.115.015308.
    [9]
    TALUKDAR S, ZHOU Y, LI D, et al. A long-acting FGF21 molecule, PF-05231023, decreases body weight and improves lipid profile in non-human primates and type 2 diabetic subjects[J]. Cell Metab, 2016, 23(3): 427-440. DOI: 10.1016/j.cmet.2016.02.001.
    [10]
    WONG V, ADAMS LA. Fibroblast growth factor 21 for non-alcoholic steatohepatitis[J]. Lancet, 2019, 392(10165): 2658-2660. DOI: 10.1016/S0140-6736(18)32165-2.
    [11]
    GOETZ R, BEENKEN A, IBRAHIMI OA, et al. Molecular insights into the klotho-dependent, endocrine mode of action of fibroblast growth factor 19 subfamily members[J]. Mol Cell Biol, 2007, 27(9): 3417-3428. DOI: 10.1128/MCB.02249-06.
    [12]
    FON TACER K, BOOKOUT AL, DING X, et al. Research resource: Comprehensive expression atlas of the fibroblast growth factor system in adult mouse[J]. Mol Endocrinol, 2010, 24(10): 2050-2064. DOI: 10.1210/me.2010-0142.
    [13]
    LIN Z, TIAN H, LAM KS, et al. Adiponectin mediates the metabolic effects of FGF21 on glucose homeostasis and insulin sensitivity in mice[J]. Cell Metab, 2013, 17(5): 779-789. DOI: 10.1016/j.cmet.2013.04.005.
    [14]
    BADMAN MK, KOESTER A, FLIER JS, et al. Fibroblast growth factor 21-deficient mice demonstrate impaired adaptation to ketosis[J]. Endocrinology, 2009, 150(11): 4931-4940. DOI: 10.1210/en.2009-0532.
    [15]
    GONG Q, HU Z, ZHANG F, et al. Fibroblast growth factor 21 improves hepatic insulin sensitivity by inhibiting mammalian target of rapamycin complex 1 in mice[J]. Hepatology, 2016, 64(2): 425-438. DOI: 10.1002/hep.28523.
    [16]
    POTTHOFF MJ, INAGAKI T, SATAPATI S, et al. FGF21 induces PGC-1alpha and regulates carbohydrate and fatty acid metabolism during the adaptive starvation response[J]. Proc Natl Acad Sci U S A, 2009, 106(26): 10853-10858. DOI: 10.1073/pnas.0904187106.
    [17]
    LIU Y, ZHAO C, XIAO J, et al. Fibroblast growth factor 21 deficiency exacerbates chronic alcohol-induced hepatic steatosis and injury[J]. Sci Rep, 2016, 6: 31026. DOI: 10.1038/srep31026.
    [18]
    KIM SH, KIM KH, KIM HK, et al. Fibroblast growth factor 21 participates in adaptation to endoplasmic reticulum stress and attenuates obesity-induced hepatic metabolic stress[J]. Diabetologia, 2015, 58(4): 809-818. DOI: 10.1007/s00125-014-3475-6.
    [19]
    XU P, ZHANG Y, LIU Y, et al. Fibroblast growth factor 21 attenuates hepatic fibrogenesis through TGF-β/smad2/3 and NF-κB signaling pathways[J]. Toxicol Appl Pharmacol, 2016, 290: 43-53. DOI: 10.1016/j.taap.2015.11.012.
    [20]
    YE D, WANG Y, LI H, et al. Fibroblast growth factor 21 protects against acetaminophen-induced hepatotoxicity by potentiating peroxisome proliferator-activated receptor coactivator protein-1α-mediated antioxidant capacity in mice[J]. Hepatology, 2014, 60(3): 977-989. DOI: 10.1002/hep.27060.
    [21]
    FOLTZ IN, HU S, KING C, et al. Treating diabetes and obesity with an FGF21-mimetic antibody activating the βKlotho/FGFR1c receptor complex[J]. Sci Transl Med, 2012, 4(162): 162ra153. DOI: 10.1126/scitranslmed.3004690.
    [22]
    FISHER FM, ESTALL JL, ADAMS AC, et al. Integrated regulation of hepatic metabolism by fibroblast growth factor 21 (FGF21) in vivo[J]. Endocrinology, 2011, 152(8): 2996-3004. DOI: 10.1210/en.2011-0281.
    [23]
    LAN T, MORGAN DA, RAHMOUNI K, et al. FGF19, FGF21, and an FGFR1/β-Klotho-activating antibody act on the nervous system to regulate body weight and glycemia[J]. Cell Metab, 2017, 26(5): 709-718. e3. DOI: 10.1016/j.cmet.2017.09.005.
    [24]
    DUSHAY J, CHUI PC, GOPALAKRISHNAN GS, et al. Increased fibroblast growth factor 21 in obesity and nonalcoholic fatty liver disease[J]. Gastroenterology, 2010, 139(2): 456-463. DOI: 10.1053/j.gastro.2010.04.054.
    [25]
    FISHER FM, CHUI PC, ANTONELLIS PJ, et al. Obesity is a fibroblast growth factor 21 (FGF21)-resistant state[J]. Diabetes, 2010, 59(11): 2781-2789. DOI: 10.2337/db10-0193.
    [26]
    YILMAZ Y, EREN F, YONAL O, et al. Increased serum FGF21 levels in patients with nonalcoholic fatty liver disease[J]. Eur J Clin Invest, 2010, 40(10): 887-892. DOI: 10.1111/j.1365-2362.2010.02338.x.
    [27]
    LI H, FANG Q, GAO F, et al. Fibroblast growth factor 21 levels are increased in nonalcoholic fatty liver disease patients and are correlated with hepatic triglyceride[J]. J Hepatol, 2010, 53(5): 934-940. DOI: 10.1016/j.jhep.2010.05.018.
    [28]
    LI H, DONG K, FANG Q, et al. High serum level of fibroblast growth factor 21 is an independent predictor of non-alcoholic fatty liver disease: A 3-year prospective study in China[J]. J Hepatol, 2013, 58(3): 557-563. DOI: 10.1016/j.jhep.2012.10.029.
    [29]
    TUCKER B, MCCLELLAND RL, ALLISON MA, et al. Relationship of fibroblast growth factor 21 levels with inflammation, lipoproteins and non-alcoholic fatty liver disease[J]. Atherosclerosis, 2020, 299: 38-44. DOI: 10.1016/j.atherosclerosis.2020.03.009.
    [30]
    YANG M, XU D, LIU Y, et al. Combined serum biomarkers in non-invasive diagnosis of non-alcoholic steatohepatitis[J]. PLoS One, 2015, 10(6): e0131664. DOI: 10.1371/journal.pone.0131664.
    [31]
    BARB D, BRIL F, KALAVALAPALLI S, et al. Plasma fibroblast growth factor 21 is associated with severity of nonalcoholic steatohepatitis in patients with obesity and type 2 diabetes[J]. J Clin Endocrinol Metab, 2019, 104(8): 3327-3336. DOI: 10.1210/jc.2018-02414.
    [32]
    WU L, PAN Q, WU G, et al. Diverse changes of circulating fibroblast growth factor 21 levels in hepatitis B virus-related diseases[J]. Sci Rep, 2017, 7(1): 16482. DOI: 10.1038/s41598-017-16312-6.
    [33]
    YE D, LI H, WANG Y, et al. Circulating fibroblast growth factor 21 is a sensitive biomarker for severe ischemia/reperfusion injury in patients with liver transplantation[J]. Sci Rep, 2016, 6: 19776. DOI: 10.1038/srep19776.
    [34]
    GILLUM MP, POTTHOFF MJ. FAP finds FGF21 easy to digest[J]. Biochem J, 2016, 473(9): 1125-1127. DOI: 10.1042/BCJ20160004.
    [35]
    CHARLES ED, NEUSCHWANDER-TETRI BA, PABLO FRIAS J, et al. Pegbelfermin (BMS-986036), PEGylated FGF21, in patients with obesity and type 2 diabetes: Results from a randomized phase 2 study[J]. Obesity (Silver Spring), 2019, 27(1): 41-49. DOI: 10.1002/oby.22344.
    [36]
    STANISLAUS S, HECHT R, YIE J, et al. A novel Fc-FGF21 with improved resistance to proteolysis, increased affinity toward β-Klotho, and enhanced efficacy in mice and cynomolgus monkeys[J]. Endocrinology, 2017, 158(5): 1314-1327. DOI: 10.1210/en.2016-1917.
    [37]
    RITCHIE M, HANOUNEH IA, NOUREDDIN M, et al. Fibroblast growth factor (FGF)-21 based therapies: A magic bullet for nonalcoholic fatty liver disease (NAFLD)?[J]. Expert Opin Investig Drugs, 2020, 29(2): 197-204. DOI: 10.1080/13543784.2020.1718104.
    [38]
    STEPHEN AH, PETER JR, BRADLEY LF, et al. Efruxifermin (efx), a long-acting fc-fgf21 fusion protein, administered for 16 weeks to patients with nash substantially reduces liver fat and alt, and improves liver histology: Analysis of a randomized, placebo-controlled, phase 2a study (BALANCED)//AASLD Abstracts (Oral)[J]. Hepatology, 2020, 72, 1(Suppl): 6A-7A. DOI: 10.1002/hep.31578.
    [39]
    BARUCH A, WONG C, CHINN LW, et al. Antibody-mediated activation of the FGFR1/Klothoβ complex corrects metabolic dysfunction and alters food preference in obese humans[J]. Proc Natl Acad Sci U S A, 2020, 117(46): 28992-29000. DOI: 10.1073/pnas.2012073117.
    [40]
    Late-breaking abstracts-presented at the 70th Annual Meeting of the American Association for the Study of Liver Diseases: The liver meetingTM 2019[J]. Hepatology, 2019, 70(6): 1477A-1501A. DOI: 10.1002/hep.31033.
    [41]
    DEPAOLI A, PHUNG V, BASHIR MR, et al. 140-LB: NGM313, a novel activator of b-Klotho/FGFR1c, improves insulin resistance and reduces hepatic fat in obese, nondiabetic subjects[J]. Diabetes, 2019, 68(Suppl 1): 140-LB.
    [42]
    GAICH G, CHIEN JY, FU H, et al. The effects of LY2405319, an FGF21 analog, in obese human subjects with type 2 diabetes[J]. Cell Metab, 2013, 18(3): 333-340. DOI: 10.1016/j.cmet.2013.08.005.
    [43]
    GENG L, LAM K, XU A. The therapeutic potential of FGF21 in metabolic diseases: From bench to clinic[J]. Nat Rev Endocrinol, 2020, 16(11): 654-667. DOI: 10.1038/s41574-020-0386-0.
    [44]
    WEI W, DUTCHAK PA, WANG X, et al. Fibroblast growth factor 21 promotes bone loss by potentiating the effects of peroxisome proliferator-activated receptor γ[J]. Proc Natl Acad Sci U S A, 2012, 109(8): 3143-3148. DOI: 10.1073/pnas.1200797109.
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