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Review Article | Open Access

FGF21-mediated autophagy: Remodeling the homeostasis in response to stress in liver diseases

Wei Shena,b,c,d,,1, Modan Yanga,b,c,d,1, Hao Chena,b,c,d,1, Chiyu Hea,b,c,d, Huigang Lia,b,c,d, Xinyu Yanga,b,c,d, Jianyong Zhuoa,b,c,d, Zuyuan Lina,b,c,d, Zhihang Hua,b,c,d, Di Lua,b,c,d( ), Xiao Xua,c,d,e( )
Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China
Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310006, China
The Institute for Organ Repair and Regenerative Medicine of Hangzhou, Hangzhou, Zhejiang 310006, China
Institute of Organ Transplantation, Zhejiang University, Hangzhou, Zhejiang 310003, China
National Center for Healthcare Quality Management in Liver Transplant, Hangzhou, Zhejiang 310003, China

Peer review under responsibility of Chongqing Medical University.

1 These authors contributed equally to this work.

Show Author Information

Abstract

Liver diseases are worldwide problems closely associated with various stresses, such as endoplasmic reticulum stress. The exact interplay between stress and liver diseases remains unclear. Autophagy plays an essential role in maintaining homeostasis, and recent studies indicate tight crosstalk between stress and autophagy in liver diseases. Once the balance between damage and autophagy is broken, autophagy can no longer resist injury or maintain homeostasis. In recent years, FGF21 (fibroblast growth factor 21)-induced autophagy has attracted much attention. FGF21 is regarded as a stress hormone and can be up-regulated by an abundance of signaling pathways in response to stress. Also, increased FGF21 activates autophagy by a complicated signaling network in which mTOR plays a pivotal role. This review summarizes the mechanism of FGF21-mediated autophagy and its derived application in the defense of stress in liver diseases and offers a glimpse into its promising prospect in future clinical practice.

Keywords

StressAutophagymTORLiver diseasesFibroblast growth factor 21

References

1

Trefts E, Gannon M, Wasserman DH. The liver. Curr Biol. 2017;27(21):R1147–R1151.
Crossref Google Scholar
2

Bajaj JS. Alcohol, liver disease and the gut microbiota. Nat Rev Gastroenterol Hepatol. 2019;16(4):235–246.
Crossref Google Scholar
3

Liang TJ. Hepatitis B: the virus and disease. Hepatology. 2009;49(5 Suppl):S13–S21.
Crossref Google Scholar
4

Powell EE, Wong VWS, Rinella M. Non-alcoholic fatty liver disease. Lancet. 2021;397(10290):2212–2224.
Crossref Google Scholar
5

Shimizu M, Sato R. Endocrine fibroblast growth factors in relation to stress signaling. Cells. 2022;11(3):505.
Crossref Google Scholar
6

Luo Y, Ye S, Li X, Lu W. Emerging structure-function paradigm of endocrine FGFs in metabolic diseases. Trends Pharmacol Sci. 2019;40(2):142–153.
Crossref Google Scholar
7

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. Cell Metabol. 2017;26(5):709–718.e3.
Crossref Google Scholar
8

Yang X, Lu D, Wang R, et al. Single-cell profiling reveals distinct immune phenotypes that contribute to ischaemia-reperfusion injury after steatotic liver transplantation. Cell Prolif. 2021;54(10):e13116.
Crossref Google Scholar
9

Domart MC, Esposti DD, Sebagh M, et al. Concurrent induction of necrosis, apoptosis, and autophagy in ischemic preconditioned human livers formerly treated by chemotherapy. J Hepatol. 2009;51(5):881–889.
Crossref Google Scholar
10

Bystrom P, Foley N, Toledo-Pereyra L, Quesnelle K. Ischemic preconditioning modulates ROS to confer protection in liver ischemia and reperfusion. Excli J. 2017;16:483–496.
Google Scholar
11

Jakubauskiene L, Jakubauskas M, Stiegler P, Leber B, Schemmer P, Strupas K. Ischemic preconditioning for liver transplantation: a systematic review and meta-analysis of randomized controlled trials. Visc Med. 2021;37(5):329–337.
Crossref Google Scholar
12

Cursio R, Colosetti P, Gugenheim J. Autophagy and liver ischemia-reperfusion injury. BioMed Res Int. 2015;2015:417590.
Crossref Google Scholar
13

Mohamed DZ, El-Sisi AEE, Sokar SS, Shebl AM, Abu-Risha SE. Targeting autophagy to modulate hepatic ischemia/reperfusion injury: a comparative study between octreotide and melatonin as autophagy modulators through AMPK/PI3K/AKT/mTOR/ULK1 and Keap1/Nrf2 signaling pathways in rats. Eur J Pharmacol. 2021;897:173920.
Crossref Google Scholar
14

Liu T, Zhang Q, Mo W, et al. The protective effects of shikonin on hepatic ischemia/reperfusion injury are mediated by the activation of the PI3K/Akt pathway. Sci Rep. 2017;7:44785.
Crossref Google Scholar
15

Heras-Sandoval D, Pérez-Rojas JM, Hernández-Damián J, Pedraza-Chaverri J. The role of PI3K/AKT/mTOR pathway in the modulation of autophagy and the clearance of protein aggregates in neurodegeneration. Cell Signal. 2014;26(12):2694–2701.
Crossref Google Scholar
16

Fouraschen SM, de Ruiter PE, Kwekkeboom J, et al. mTOR signaling in liver regeneration: rapamycin combined with growth factor treatment. World J Transplant. 2013;3(3):36–47.
Crossref Google Scholar
17

Nagy LE, Ding WX, Cresci G, Saikia P, Shah VH. Linking pathogenic mechanisms of alcoholic liver disease with clinical phenotypes. Gastroenterology. 2016;150(8):1756–1768.
Crossref Google Scholar
18

Eid N, Ito Y, Horibe A, Otsuki Y. Ethanol-induced mitophagy in liver is associated with activation of the PINK1-Parkin pathway triggered by oxidative DNA damage. Histol Histopathol. 2016;31(10):1143–1159.
Google Scholar
19

Williams JA, Ni HM, Ding Y, Ding WX. Parkin regulates mitophagy and mitochondrial function to protect against alcohol-induced liver injury and steatosis in mice. Am J Physiol Gastrointest Liver Physiol. 2015;309(5):G324–G340.
Crossref Google Scholar
20

Ni HM, Du K, You M, Ding WX. Critical role of FoxO3a in alcohol-induced autophagy and hepatotoxicity. Am J Pathol. 2013;183(6):1815–1825.
Crossref Google Scholar
21

Ni HM, Bhakta A, Wang S, et al. Role of hypoxia inducing factor-1β in alcohol-induced autophagy, steatosis and liver injury in mice. PLoS One. 2014;9(12):e115849.
Crossref Google Scholar
22

Ding WX, Li M, Chen X, et al. Autophagy reduces acute ethanol-induced hepatotoxicity and steatosis in mice. Gastroenterology. 2010;139(5):1740–1752.
Crossref Google Scholar
23

Lin CW, Zhang H, Li M, et al. Pharmacological promotion of autophagy alleviates steatosis and injury in alcoholic and non-alcoholic fatty liver conditions in mice. J Hepatol. 2013;58(5):993–999.
Crossref Google Scholar
24

Li Y, Ni HM, Jaeschke H, Ding WX. Chlorpromazine protects against acetaminophen-induced liver injury in mice by modulating autophagy and c-Jun N-terminal kinase activation. Liver Res. 2019;3(1):65–74.
Crossref Google Scholar
25

Shan S, Shen Z, Zhang C, Kou R, Xie K, Song F. Mitophagy protects against acetaminophen-induced acute liver injury in mice through inhibiting NLRP3 inflammasome activation. Biochem Pharmacol. 2019;169:113643.
Crossref Google Scholar
26

Wang H, Ni HM, Chao X, et al. Double deletion of PINK1 and Parkin impairs hepatic mitophagy and exacerbates acetaminophen-induced liver injury in mice. Redox Biol. 2019;22:101148.
Crossref Google Scholar
27

Ilyas G, Zhao E, Liu K, et al. Macrophage autophagy limits acute toxic liver injury in mice through down regulation of interleukin-1β. J Hepatol. 2016;64(1):118–127.
Crossref Google Scholar
28

Klionsky DJ, Petroni G, Amaravadi RK, et al. Autophagy in major human diseases. EMBO J. 2021;40(19):e108863.
Crossref Google Scholar
29

Eslam M, Sanyal AJ, George J. MAFLD: a consensus-driven proposed nomenclature for metabolic associated fatty liver disease. Gastroenterology. 2020;158(7):1999–2014.e1.
Crossref Google Scholar
30

Yamamura S, Eslam M, Kawaguchi T, et al. MAFLD identifies patients with significant hepatic fibrosis better than NAFLD. Liver Int. 2020;40(12):3018–3030.
Crossref Google Scholar
31

Zhang X, Han J, Man K, et al. CXC chemokine receptor 3 promotes steatohepatitis in mice through mediating inflammatory cytokines, macrophages and autophagy. J Hepatol. 2016;64(1):160–170.
Crossref Google Scholar
32

Day CP, James OFW. Steatohepatitis: a tale of two “hits”. Gastroenterology. 1998;114(4):842–845.
Crossref Google Scholar
33

Donnelly KL, Smith CI, Schwarzenberg SJ, Jessurun J, Boldt MD, Parks EJ. Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease. J Clin Invest. 2005;115(5):1343–1351.
Crossref Google Scholar
34

Zechner R, Zimmermann R, Eichmann TO, et al. FAT SIGNALS: lipases and lipolysis in lipid metabolism and signaling. Cell Metabol. 2012;15(3):279–291.
Crossref Google Scholar
35

Olzmann JA, Carvalho P. Dynamics and functions of lipid droplets. Nat Rev Mol Cell Biol. 2019;20(3):137–155.
Crossref Google Scholar
36

Angelini C, Nascimbeni AC, Cenacchi G, Tasca E. Lipolysis and lipophagy in lipid storage myopathies. Biochim Biophys Acta. 2016;1862(7):1367–1373.
Crossref Google Scholar
37

Tao T, Xu H. Autophagy and obesity and diabetes. Adv Exp Med Biol. 2020;1207:445–461.
Crossref Google Scholar
38

Martinez-Lopez N, Singh R. Autophagy and lipid droplets in the liver. Annu Rev Nutr. 2015;35:215–237.
Crossref Google Scholar
39

Zubiete-Franco I, García-Rodríguez JL, Martínez-Uña M, et al. Methionine and S-adenosylmethionine levels are critical regulators of PP2A activity modulating lipophagy during steatosis. J Hepatol. 2016;64(2):409–418.
Crossref Google Scholar
40

Liu HY, Han J, Cao SY, et al. Hepatic autophagy is suppressed in the presence of insulin resistance and hyperinsulinemia. J Biol Chem. 2009;284(45):31484–31492.
Crossref Google Scholar
41

Liu K, Zhao E, Ilyas G, et al. Impaired macrophage autophagy increases the immune response in obese mice by promoting proinflammatory macrophage polarization. Autophagy. 2015;11(2):271–284.
Crossref Google Scholar
42

Lodder J, Denaës T, Chobert MN, et al. Macrophage autophagy protects against liver fibrosis in mice. Autophagy. 2015;11(8):1280–1292.
Crossref Google Scholar
43

Thoen LF, Guimarães EL, Dollé L, et al. A role for autophagy during hepatic stellate cell activation. J Hepatol. 2011;55(6):1353–1360.
Crossref Google Scholar
44

Fu MY, He YJ, Lv X, et al. Transforming growth factor-β1 reduces apoptosis via autophagy activation in hepatic stellate cells. Mol Med Rep. 2014;10(3):1282–1288.
Crossref Google Scholar
45

Hernández-Gea V, Ghiassi-Nejad Z, Rozenfeld R, et al. Autophagy releases lipid that promotes fibrogenesis by activated hepatic stellate cells in mice and in human tissues. Gastroenterology. 2012;142(4):938–946.
Crossref Google Scholar
46

Ruart M, Chavarria L, Campreciós G, et al. Impaired endothelial autophagy promotes liver fibrosis by aggravating the oxidative stress response during acute liver injury. J Hepatol. 2019;70(3):458–469.
Crossref Google Scholar
47

Schulze RJ, Rasineni K, Weller SG, et al. Ethanol exposure inhibits hepatocyte lipophagy by inactivating the small guanosine triphosphatase Rab7. Hepatol Commun. 2017;1(2):140–152.
Crossref Google Scholar
48

Takamura A, Komatsu M, Hara T, et al. Autophagy-deficient mice develop multiple liver tumors. Genes Dev. 2011;25(8):795–800.
Crossref Google Scholar
49

Ni HM, Woolbright BL, Williams J, et al. Nrf2 promotes the development of fibrosis and tumorigenesis in mice with defective hepatic autophagy. J Hepatol. 2014;61(3):617–625.
Crossref Google Scholar
50

Umemura A, He F, Taniguchi K, et al. p62, upregulated during preneoplasia, induces hepatocellular carcinogenesis by maintaining survival of stressed HCC-initiating cells. Cancer Cell. 2016;29(6):935–948.
Crossref Google Scholar
51

Tacke F, Trautwein C. Controlling autophagy: a new concept for clearing liver disease. Hepatology. 2011;53(1):356–358.
Crossref Google Scholar
52

Tang Y, Blomenkamp KS, Fickert P, Trauner M, Teckman JH. NorUDCA promotes degradation of α1-antitrypsin mutant Z protein by inducing autophagy through AMPK/ULK1 pathway. PLoS One. 2018;13(8):e0200897.
Crossref Google Scholar
53

Polishchuk EV, Merolla A, Lichtmannegger J, et al. Activation of autophagy, observed in liver tissues from patients with Wilson disease and from ATP7B-deficient animals, protects hepatocytes from copper-induced apoptosis. Gastroenterology. 2019;156(4):1173–1189.e5.
Crossref Google Scholar
54

Sir D, Tian Y, Chen WL, Ann DK, Yen TS, Ou JH. The early autophagic pathway is activated by hepatitis B virus and required for viral DNA replication. Proc Natl Acad Sci U S A. 2010;107(9):4383–4388.
Crossref Google Scholar
55

Khan M, Imam H, Siddiqui A. Subversion of cellular autophagy during virus infection: insights from hepatitis B and hepatitis C viruses. Liver Res. 2018;2(3):146–156.
Crossref Google Scholar
56

Lebeaupin C, Vallée D, Hazari Y, Hetz C, Chevet E, Bailly-Maitre B. Endoplasmic reticulum stress signalling and the pathogenesis of non-alcoholic fatty liver disease. J Hepatol. 2018;69(4):927–947.
Crossref Google Scholar
57

Senft D, Ronai ZA. UPR, autophagy, and mitochondria crosstalk underlies the ER stress response. Trends Biochem Sci. 2015;40(3):141–148.
Crossref Google Scholar
58

De Sousa-Coelho AL, Marrero PF, Haro D. Activating transcription factor 4-dependent induction of FGF21 during amino acid deprivation. Biochem J. 2012;443(1):165–171.
Crossref Google Scholar
59

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. Diabetologia. 2015;58(4):809–818.
Crossref Google Scholar
60

Zarei M, Barroso E, Leiva R, et al. Heme-regulated eIF2α kinase modulates hepatic FGF21 and is activated by PPARβ/δ deficiency. Diabetes. 2016;65(10):3185–3199.
Crossref Google Scholar
61

Kim KH, Jeong YT, Kim SH, et al. Metformin-induced inhibition of the mitochondrial respiratory chain increases FGF21 expression via ATF4 activation. Biochem Biophys Res Commun. 2013;440(1):76–81.
Crossref Google Scholar
62

Kim KH, Jeong YT, Oh H, et al. Autophagy deficiency leads to protection from obesity and insulin resistance by inducing Fgf21 as a mitokine. Nat Med. 2013;19(1):83–92.
Crossref Google Scholar
63

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 Metabol. 2007;5(6):426–437.
Crossref Google Scholar
64

Inagaki T, Dutchak P, Zhao G, et al. Endocrine regulation of the fasting response by PPARα-mediated induction of fibroblast growth factor 21. Cell Metabol. 2007;5(6):415–425.
Crossref Google Scholar
65

He F, Ru X, Wen T. NRF2, a transcription factor for stress response and beyond. Int J Mol Sci. 2020;21(13):4777.
Crossref Google Scholar
66

Chen J, Jiang S, Shao H, et al. CRISPR-Cas9-based genome-wide screening identified novel targets for treating sorafenib-resistant hepatocellular carcinoma: a cross-talk between FGF21 and the NRF2 pathway. Sci China Life Sci. 2022;65(10):1998–2016.
Crossref Google Scholar
67

Furusawa Y, Uruno A, Yagishita Y, Higashi C, Yamamoto M. Nrf2 induces fibroblast growth factor 21 in diabetic mice. Gene Cell. 2014;19(12):864–878.
Crossref Google Scholar
68

Asrih M, Veyrat-Durebex C, Poher AL, Lyautey J, Rohner-Jeanrenaud F, Jornayvaz FR. Leptin as a potential regulator of FGF21. Cell Physiol Biochem. 2016;38(3):1218–1225.
Crossref Google Scholar
69

Packer M. Cardioprotective effects of sirtuin-1 and its downstream effectors: potential role in mediating the heart failure benefits of SGLT2 (sodium-glucose cotransporter 2) inhibitors. Circ Heart Fail. 2020;13(9):e007197.
Crossref Google Scholar
70

Izumiya Y, Bina HA, Ouchi N, Akasaki Y, Kharitonenkov A, Walsh K. FGF21 is an Akt-regulated myokine. FEBS Lett. 2008;582(27):3805–3810.
Crossref Google Scholar
71

Hanks LJ, Gutiérrez OM, Bamman MM, Ashraf A, McCormick KL, Casazza K. Circulating levels of fibroblast growth factor-21 increase with age independently of body composition indices among healthy individuals. J Clin Transl Endocrinol. 2015;2(2):77–82.
Crossref Google Scholar
72

Wang Y, Solt LA, Burris TP. Regulation of FGF21 expression and secretion by retinoic acid receptor-related orphan receptor α. J Biol Chem. 2010;285(21):15668–15673.
Crossref Google Scholar
73

Laplante M, Sabatini DM. mTOR signaling at a glance. J Cell Sci. 2009;122(pt 20):3589–3594.
Crossref Google Scholar
74

Morita M, Gravel SP, Hulea L, et al. mTOR coordinates protein synthesis, mitochondrial activity and proliferation. Cell Cycle. 2015;14(4):473–480.
Crossref Google Scholar
75

Gao G, Chen W, Yan M, et al. Rapamycin regulates the balance between cardiomyocyte apoptosis and autophagy in chronic heart failure by inhibiting mTOR signaling. Int J Mol Med. 2020;45(1):195–209.
Crossref Google Scholar
76

Szwed A, Kim E, Jacinto E. Regulation and metabolic functions of mTORC1 and mTORC2. Physiol Rev. 2021;101(3):1371–1426.
Crossref Google Scholar
77

Wang L, Harris TE, Roth RA, Lawrence JC. PRAS40 regulates mTORC1 kinase activity by functioning as a direct inhibitor of substrate binding. J Biol Chem. 2007;282(27):20036–20044.
Crossref Google Scholar
78

Shimobayashi M, Hall MN. Making new contacts: the mTOR network in metabolism and signalling crosstalk. Nat Rev Mol Cell Biol. 2014;15(3):155–162.
Crossref Google Scholar
79

Laplante M, Sabatini DM. Regulation of mTORC1 and its impact on gene expression at a glance. J Cell Sci. 2013;126(pt 8):1713–1719.
Crossref Google Scholar
80

Herzig S, Shaw RJ. AMPK: guardian of metabolism and mitochondrial homeostasis. Nat Rev Mol Cell Biol. 2018;19(2):121–135.
Crossref Google Scholar
81

Salminen A, Kauppinen A, Kaarniranta K. FGF21 activates AMPK signaling: impact on metabolic regulation and the aging process. J Mol Med (Berl). 2017;95(2):123–131.
Crossref Google Scholar
82

Zhou K, Chen H, Lin J, et al. FGF21 augments autophagy in random-pattern skin flaps via AMPK signaling pathways and improves tissue survival. Cell Death Dis. 2019;10(12):872.
Crossref Google Scholar
83

Qiang W, Shen T, Noman M, et al. Fibroblast growth factor 21 augments autophagy and reduces apoptosis in damaged liver to improve tissue regeneration in zebrafish. Front Cell Dev Biol. 2021;9:756743.
Crossref Google Scholar
84

Chen F, Zhan J, Yan X, et al. FGF21 alleviates microvascular damage following limb ischemia/reperfusion injury by TFEB-mediated autophagy enhancement and anti-oxidative response. Signal Transduct Targeted Ther. 2022;7(1):349.
Crossref Google Scholar
85

Kim HK, Lee GH, Bhattarai KR, et al. TMBIM6 (transmembrane BAX inhibitor motif containing 6) enhances autophagy through regulation of lysosomal calcium. Autophagy. 2021;17(3):761–778.
Crossref Google Scholar
86

Gao Y, Zhang W, Zeng LQ, et al. Exercise and dietary intervention ameliorate high-fat diet-induced NAFLD and liver aging by inducing lipophagy. Redox Biol. 2020;36:101635.
Crossref Google Scholar
87

Lu H, Jia C, Wu D, et al. Fibroblast growth factor 21 (FGF21) alleviates senescence, apoptosis, and extracellular matrix degradation in osteoarthritis via the SIRT1-mTOR signaling pathway. Cell Death Dis. 2021;12(10):865.
Crossref Google Scholar
88

Zhang X, Cheng X, Yu L, et al. MCOLN1 is a ROS sensor in lysosomes that regulates autophagy. Nat Commun. 2016;7:12109.
Crossref Google Scholar
89

Zhang Y, Liu D, Long XX, Fang QC, Jia WP, Li HT. The role of FGF21 in the pathogenesis of cardiovascular disease. Chin Med J. 2021;134(24):2931–2943.
Crossref Google Scholar
90

Meng F, Cao Y, Khoso MH, et al. Therapeutic effect and mechanism of combined use of FGF21 and insulin on diabetic nephropathy. Arch Biochem Biophys. 2021;713:109063.
Crossref Google Scholar
91

Straub LG, Scherer PE. Metabolic messengers: adiponectin. Nat Metab. 2019;1(3):334–339.
Crossref Google Scholar
92

Chung SJ, Nagaraju GP, Nagalingam A, et al. ADIPOQ/adiponectin induces cytotoxic autophagy in breast cancer cells through STK11/LKB1-mediated activation of the AMPK-ULK1 axis. Autophagy. 2017;13(8):1386–1403.
Crossref Google Scholar
93

Wang L, Luo Y, Luo L, et al. Adiponectin restrains ILC2 activation by AMPK-mediated feedback inhibition of IL-33 signaling. J Exp Med. 2021;218(2):e20191054.
Crossref Google Scholar
94

Cooke D, Mattocks D, Nichenametla SN, Anunciado-Koza RP, Koza RA, Ables GP. Weight loss and concomitant adipose autophagy in methionine-restricted obese mice is not dependent on adiponectin or FGF21. Obesity. 2020;28(6):1075–1085.
Crossref Google Scholar
95

Ruderman NB, Xu XJ, Nelson L, et al. AMPK and SIRT1: a long-standing partnership? Am J Physiol Endocrinol Metab. 2010;298(4):E751–E760.
Crossref Google Scholar
96

Lee IH, Cao L, Mostoslavsky R, et al. A role for the NAD-dependent deacetylase Sirt1 in the regulation of autophagy. Proc Natl Acad Sci U S A. 2008;105(9):3374–3379.
Crossref Google Scholar
97

Zhang H, Zhang W, Yun D, et al. Alternate-day fasting alleviates diabetes-induced glycolipid metabolism disorders: roles of FGF21 and bile acids. J Nutr Biochem. 2020;83:108403.
Crossref Google Scholar
98

Yang X, Jin Z, Lin D, et al. FGF21 alleviates acute liver injury by inducing the SIRT1-autophagy signalling pathway. J Cell Mol Med. 2022;26(3):868–879.
Crossref Google Scholar
99

Isaacs-Ten A, Moreno-Gonzalez M, Bone C, et al. Metabolic regulation of macrophages by SIRT1 determines activation during cholestatic liver disease in mice. Cell Mol Gastroenterol Hepatol. 2022;13(4):1019–1039.
Crossref Google Scholar
100

Zhao Y, Mao A, Zhang R, Guan S, Lu J. SIRT1/mTOR pathway-mediated autophagy dysregulation promotes Pb-induced hepatic lipid accumulation in HepG2 cells. Environ Toxicol. 2022;37(3):549–563.
Crossref Google Scholar
101

Zhang CY, Tan XH, Yang HH, et al. COX-2/sEH dual inhibitor alleviates hepatocyte senescence in NAFLD mice by restoring autophagy through Sirt1/PI3K/AKT/mTOR. Int J Mol Sci. 2022;23(15):8267.
Crossref Google Scholar
102

Dai H, Hu W, Zhang L, et al. FGF21 facilitates autophagy in prostate cancer cells by inhibiting the PI3K-Akt-mTOR signaling pathway. Cell Death Dis. 2021;12(4):303.
Crossref Google Scholar
103

Zheng J, Ma X, Zhou Y, et al. GATA2/FGF21 axis regulates the effects of high glucose on the apoptosis, autophagy and oxidative stress of human umbilical vein endothelial cell via PI3K/AKT/mTOR pathway. Ann Clin Lab Sci. 2022;52(2):278–291.
Google Scholar
104

Shen JZ, Wu G, Guo S. Amino acids in autophagy: regulation and function. Adv Exp Med Biol. 2021;1332:51–66.
Crossref Google Scholar
105

Zhang Y, Higgins CB, van Tine BA, Bomalaski JS, DeBosch BJ. Pegylated arginine deiminase drives arginine turnover and systemic autophagy to dictate energy metabolism. Cell Rep Med. 2022;3(1):100498.
Crossref Google Scholar
106

Ferrer-Curriu G, Guitart-Mampel M, Rupérez C, et al. The protective effect of fibroblast growth factor-21 in alcoholic cardiomyopathy: a role in protecting cardiac mitochondrial function. J Pathol. 2021;253(2):198–208.
Crossref Google Scholar
107

Kim MJ, Febbraro D, Farkona S, et al. Distinct roles of UVRAG and EGFR signaling in skeletal muscle homeostasis. Mol Metabol. 2021;47:101185.
Crossref Google Scholar
108

Tucker B, Li H, Long X, Rye KA, Ong KL. Fibroblast growth factor 21 in non-alcoholic fatty liver disease. Metabolism. 2019;101:153994.
Crossref Google Scholar
109

Yang C, Lu W, Lin T, et al. Activation of liver FGF21 in hepatocarcinogenesis and during hepatic stress. BMC Gastroenterol. 2013;13:67.
Crossref Google Scholar
110

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 Hepatol. 2010;53(5):934–940.
Crossref Google Scholar
111

Lee Y, Lim S, Hong ES, et al. Serum FGF21 concentration is associated with hypertriglyceridaemia, hyperinsulinaemia and pericardial fat accumulation, independently of obesity, but not with current coronary artery status. Clin Endocrinol. 2014;80(1):57–64.
Crossref Google Scholar
112

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. Sci Rep. 2016;6:19776.
Crossref Google Scholar
113

Kosola S, Lampela H, Gylling H, et al. Cholesterol metabolism altered and FGF21 levels high after pediatric liver transplantation despite normal serum lipids. Am J Transplant. 2012;12(10):2815–2824.
Crossref Google Scholar
114

Barb D, Bril F, Kalavalapalli S, Cusi K. Plasma fibroblast growth factor 21 is associated with severity of nonalcoholic steatohepatitis in patients with obesity and type 2 diabetes. J Clin Endocrinol Metab. 2019;104(8):3327–3336.
Crossref Google Scholar
115

Rajan S, Mandikian D, Baruch A, et al. Preclinical pharmacokinetic characterization of an adipose tissue-targeting monoclonal antibody in obese and non-obese animals. mAbs. 2017;9(8):1379–1388.
Crossref Google Scholar
116

Thompson KE, Guillot M, Graziano MJ, Mangipudy RS, Chadwick KD. Pegbelfermin, a PEGylated FGF21 analogue, has pharmacology without bone toxicity after 1-year dosing in skeletally-mature monkeys. Toxicol Appl Pharmacol. 2021;428:115673.
Crossref Google Scholar
117

Liu SQ, Roberts D, Kharitonenkov A, et al. Endocrine protection of ischemic myocardium by FGF21 from the liver and adipose tissue. Sci Rep. 2013;3:2767.
Crossref Google Scholar
118

Moon H, Choi JW, Song BW, et al. Brite adipocyte FGF21 attenuates cardiac ischemia/reperfusion injury in rat hearts by modulating NRF2. Cells. 2022;11(3):567.
Crossref Google Scholar
119

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. Endocrinology. 2017;158(5):1314–1327.
Crossref Google Scholar
120

Harrison SA, Ruane PJ, Freilich BL, et al. Efruxifermin in non-alcoholic steatohepatitis: a randomized, double-blind, placebo-controlled, phase 2a trial. Nat Med. 2021;27(7):1262–1271.
Crossref Google Scholar
121

Gaich G, Chien JY, Fu H, et al. The effects of LY2405319, an FGF21 analog, in obese human subjects with type 2 diabetes. Cell Metabol. 2013;18(3):333–340.
Crossref Google Scholar
122

Lee JH, Kang YE, Chang JY, et al. An engineered FGF21 variant, LY2405319, can prevent non-alcoholic steatohepatitis by enhancing hepatic mitochondrial function. Am J Transl Res. 2016;8(11):4750–4763.
Google Scholar
Genes & Diseases
Volume 11 Issue 3,
May 2024
Article number: 101027
DOI: 10.1016/j.gendis.2023.05.019
Cite this article:
Shen W, Yang M, Chen H, et al. FGF21-mediated autophagy: Remodeling the homeostasis in response to stress in liver diseases. Genes & Diseases, 2024, 11(3): 101027. https://doi.org/10.1016/j.gendis.2023.05.019

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Received: 24 February 2023
Revised: 23 April 2023
Accepted: 09 May 2023
Published: 13 July 2023
© 2023 The Authors.

This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
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