Abstract
Fibroblast growth factor (FGF) has been considered to modulate liver regeneration (LR) after partial hepatectomy (PH) at the tissue level. Previous studies have demonstrated that FGF15 and FGF19 induce the activation of its receptor, FGF receptor 4 (FGFR4), which can promote hepatocellular carcinoma progression and regulate liver lipid metabolism. In this study, we aimed to explore the role of the ileal FGF15/19- hepatic FGFR4 axis in the LR after PH. Male C57BL/6 mice aged 8–12 weeks were partially hepatectomized and assessed for expression of ileal FGF15/19 to hepatic FGFR4 signaling. We used recombinant human FGF19 protein and a small interfering RNA (siRNA) of FGFR4 to regulate expression of the FGF15/19-FGFR4 axis in vitro and in vivo. The proliferation and cell cycle of hepatocytes, the expression levels of FGF15/19-FGFR4 downstream molecules, liver recovery, and lipid metabolism were assessed. We found that both ileal and serum FGF15 expression were upregulated and hepatic FGFR4 was activated after PH in mice. FGF15/19 promoted cell cycle progression, enhanced proliferation, and reduced hepatic lipid accumulation of hepatocytes both in vitro and in vivo. Furthermore, the proliferative effect and lipid regulatory properties of FGF15/19 were dependent on FGFR4 in hepatocytes. In addition, ileal FGF15/19-hepatic FGFR4 transduction during hepatocyte proliferation was regulated by extracellular regulated protein kinase (ERK) 1/2. In conclusion, the ileal FGF15/19 to hepatic FGFR4 axis is activated and promotes LR after PH in mice, supporting the potential of ileal FGF15/19 to hepatic FGFR4 axis-targeted therapy to enhance LR after PH.
References
Akita K, Okuno M, Enya M, Imai S, Moriwaki H, Kawada N, Suzuki Y, Kojima S (2002) Impaired liver regeneration in mice by lipopolysaccharide via TNF-alpha/kallikrein-mediated activation of latent TGF-beta. Gastroenterology 123(1):352–364. https://doi.org/10.1053/gast.2002.34234
Alvarez-Sola G, Uriarte I, Latasa MU, Fernandez-Barrena MG, Urtasun R, Elizalde M, Barcena-Varela M, Jimenez M, Chang HC, Barbero R, Catalan V, Rodriguez A, Fruhbeck G, Gallego-Escuredo JM, Gavalda-Navarro A, Villarroya F, Rodriguez-Ortigosa CM, Corrales FJ, Prieto J, Berraondo P, Berasain C, Avila MA (2017) Fibroblast growth factor 15/19 (FGF15/19) protects from diet-induced hepatic steatosis: development of an FGF19-based chimeric molecule to promote fatty liver regeneration. Gut 66(10):1818–1828. https://doi.org/10.1136/gutjnl-2016-312975
Beenken A, Mohammadi M (2009) The FGF family: biology, pathophysiology and therapy. Nat Rev Drug Discov 8(3):235–253. https://doi.org/10.1038/nrd2792
Berger J, Moller DE (2002) The mechanisms of action of PPARs. Annu Rev Med 53(1):409–435. https://doi.org/10.1146/annurev.med.53.082901.104018
Bonen A, Campbell SE, Benton CR, Chabowski A, Coort SLM, Han XX, Koonen DPY (2004) Regulation of fatty acid transport by fatty acid translocase/CD36. Proc Nutr Soc 63(02):245–249. https://doi.org/10.1079/PNS2004331
Brooks AN, Kilgour E, Smith PD (2012) Molecular pathways: fibroblast growth factor signaling: a new therapeutic opportunity in cancer. Clin Cancer Res 18(7):1855–1862. https://doi.org/10.1158/1078-0432.ccr-11-0699
Chen Q, Jiang Y, An Y, Zhao N, Zhao Y, Yu C (2011) Soluble FGFR4 extracellular domain inhibits FGF19-induced activation of FGFR4 signaling and prevents nonalcoholic fatty liver disease. Biochem Biophys Res Commun 409(4):651–656. https://doi.org/10.1016/j.bbrc.2011.05.059
Choi M, Moschetta A, Bookout AL, Peng L, Umetani M, Holmstrom SR, Suino-Powell K, Xu HE, Richardson JA, Gerard RD, Mangelsdorf DJ, Kliewer SA (2006) Identification of a hormonal basis for gallbladder filling. Nat Med 12(11):1253–1255. https://doi.org/10.1038/nm1501
Ezzat S, Huang P, Dackiw A, Asa SL (2005) Dual inhibition of RET and FGFR4 restrains medullary thyroid cancer cell growth. Clin Cancer Res 11(3):1336–1341
Fausto N, Campbell JS, Riehle KJ (2006) Liver regeneration. Hepatology 43(S1):S45–S53. https://doi.org/10.1002/hep.20969
Fausto N, Campbell JS, Riehle KJ (2012) Liver regeneration. J Hepatol 57(3):692–694. https://doi.org/10.1016/j.jhep.2012.04.016
Fu L, John LM, Adams SH, Yu XX, Tomlinson E, Renz M, Williams PM, Soriano R, Corpuz R, Moffat B, Vandlen R, Simmons L, Foster J, Stephan JP, Tsai SP, Stewart TA (2004) Fibroblast growth factor 19 increases metabolic rate and reverses dietary and leptin-deficient diabetes. Endocrinology 145(6):2594–2603. https://doi.org/10.1210/en.2003-1671
Gauglhofer C, Sagmeister S, Schrottmaier W, Fischer C, Rodgarkia-Dara C, Mohr T, Stattner S, Bichler C, Kandioler D, Wrba F, Schulte-Hermann R, Holzmann K, Grusch M, Marian B, Berger W, Grasl-Kraupp B (2011) Up-regulation of the fibroblast growth factor 8 subfamily in human hepatocellular carcinoma for cell survival and neoangiogenesis. Hepatology 53(3):854–864. https://doi.org/10.1002/hep.24099
Geier A, Trautwein C (2007) Bile acids are “homeotrophic” sensors of the functional hepatic capacity and regulate adaptive growth during liver regeneration. Hepatology 45(1):251–253. https://doi.org/10.1002/hep.21521
Holt JA, Luo G, Billin AN, Bisi J, McNeill YY, Kozarsky KF, Donahee M, Wang DY, Mansfield TA, Kliewer SA, Goodwin B, Jones SA (2003) Definition of a novel growth factor-dependent signal cascade for the suppression of bile acid biosynthesis. Genes Dev 17(13):1581–1591. https://doi.org/10.1101/gad.1083503
Huang W, Ma K, Zhang J, Qatanani M, Cuvillier J, Liu J, Dong B, Huang X, Moore DD (2006) Nuclear receptor-dependent bile acid signaling is required for normal liver regeneration. Science 312(5771):233–236. https://doi.org/10.1126/science.1121435
Huang X, Yang C, Luo Y, Jin C, Wang F, Mckeehan WL (2007) FGFR4 prevents hyperlipidemia and insulin resistance but underlies high-fat diet induced fatty liver. Diabetes 56(10):2501–2510. https://doi.org/10.2337/db07-0648
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 (2005) Fibroblast growth factor 15 functions as an enterohepatic signal to regulate bile acid homeostasis. Cell Metab 2(4):217–225. https://doi.org/10.1016/j.cmet.2005.09.001
Karp SJ (2009) Clinical implications of advances in the basic science of liver repair and regeneration. Am J Transplant 9(9):1973–1980. https://doi.org/10.1111/j.1600-6143.2009.02731.x
Kir S, Beddow SA, Samuel VT, Miller P, Previs SF, Suino-Powell K, Xu HE, Shulman GI, Kliewer SA, Mangelsdorf DJ (2011) FGF19 as a postprandial, insulin-independent activator of hepatic protein and glycogen synthesis. Science 331(6024):1621–1624. https://doi.org/10.1126/science.1198363
Kong B, Huang J, Zhu Y, Li G, Williams J, Shen S, Aleksunes LM, Richardson JR, Apte U, Rudnick DA, Guo GL (2014) Fibroblast growth factor 15 deficiency impairs liver regeneration in mice. Am J Physiol Gastrointest Liver Physiol 306(10):G893–G902. https://doi.org/10.1152/ajpgi.00337.2013
Latasa MU, Salis F, Urtasun R, Garcia-Irigoyen O, Elizalde M, Uriarte I, Santamaria M, Feo F, Pascale RM, Prieto J, Berasain C, Avila MA (2012) Regulation of amphiregulin gene expression by beta-catenin signaling in human hepatocellular carcinoma cells: a novel crosstalk between FGF19 and the EGFR system. PLoS One 7(12):e52711. https://doi.org/10.1371/journal.pone.0052711
Li WC, Ralphs KL, Tosh D (2010) Isolation and culture of adult mouse hepatocytes. Methods Mol Biol 633:185–196. https://doi.org/10.1007/978-1-59745-019-5_13
Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) method. Methods 25(4):402–408. https://doi.org/10.1006/meth.2001.1262
Meng Z, Liu N, Fu X, Wang X, Wang YD, Chen WD, Zhang L, Forman BM, Huang W (2011) Insufficient bile acid signaling impairs liver repair in CYP27(−/−) mice. J Hepatol 55(4):885–895. https://doi.org/10.1016/j.jhep.2010.12.037
Michalopoulos GK (2010) Liver regeneration after partial hepatectomy: critical analysis of mechanistic dilemmas. Am J Pathol 176(1):2–13. https://doi.org/10.2353/ajpath.2010.090675
Mitchell C, Willenbring H (2008) A reproducible and well-tolerated method for 2/3 partial hepatectomy in mice. Nat Protoc 3(7):1167–1170. https://doi.org/10.1038/nprot.2008.80
Nicholes K, Guillet S, Tomlinson E, Hillan K, Wright B, Frantz GD, Pham TA, Dillard-Telm L, Tsai SP, Stephan JP, Stinson J, Stewart T, French DM (2002) A mouse model of hepatocellular carcinoma: ectopic expression of fibroblast growth factor 19 in skeletal muscle of transgenic mice. Am J Pathol 160(6):2295–2307. https://doi.org/10.1016/s0002-9440(10)61177-7
Padrissa-Altes S, Bachofner M, Bogorad RL, Pohlmeier L, Rossolini T, Bohm F, Liebisch G, Hellerbrand C, Koteliansky V, Speicher T, Werner S (2015) Control of hepatocyte proliferation and survival by Fgf receptors is essential for liver regeneration in mice. Gut 64(9):1444–1453. https://doi.org/10.1136/gutjnl-2014-307874
Roidl A, Berger HJ, Kumar S, Bange J, Knyazev P, Ullrich A (2009) Resistance to chemotherapy is associated with fibroblast growth factor receptor 4 up-regulation. Clin Cancer Res 15(6):2058–2066. https://doi.org/10.1158/1078-0432.CCR-08-0890
Rudnick DA, Davidson NO (2012) Functional relationships between lipid metabolism and liver regeneration. Int J Hepatol 2012:549241–549241. https://doi.org/10.1155/2012/549241
Satyanarayana A, Geffers R, Manns MP, Buer J, Rudolph KL (2004) Gene expression profile at the G1/S transition of liver regeneration after partial hepatectomy in mice. Cell Cycle 3(11):1405–1417. https://doi.org/10.4161/cc.3.11.1212
Sawey ET, Chanrion M, Cai C, Wu G, Zhang J, Zender L, Zhao A, Busuttil RW, Yee H, Stein L, DM F, RS F, SW L SP (2011) Identification of a therapeutic strategy targeting amplified FGF19 in liver cancer by oncogenomic screening. Cancer Cell 19(3):347–358. https://doi.org/10.1016/j.ccr.2011.01.040
Shin DJ, Osborne TF (2009) FGF15/FGFR4 integrates growth factor signaling with hepatic bile acid metabolism and insulin action. J Biol Chem 284(17):11110–11120. https://doi.org/10.1074/jbc.M808747200
Simmons Kovacs LA, Orlando DA, Haase SB (2008) Transcription networks and cyclin/CDKs: the yin and yang of cell cycle oscillators. Cell Cycle 7(17):2626–2629. https://doi.org/10.4161/cc.7.17.6515
Skov OP, Boesby S, Kirkegaard P, Therkelsen K, Almdal T, Poulsen SS, Nexø E (1988) Influence of epidermal growth factor on liver regeneration after partial hepatectomy in rats. Hepatology 8:992–996
Song E, Lee SK, Wang J, Ince N, Ouyang N, Min J, Chen J, Shankar P, Lieberman J (2003) RNA interference targeting Fas protects mice from fulminant hepatitis. Nat Med 9(3):347–351. https://doi.org/10.1038/nm828
Soutschek J, Akinc A, Bramlage B, Charisse K, Constien R, Donoghue M, Elbashir S, Geick A, Hadwiger P, Harborth J, John M, Kesavan V, Lavine G, Pandey RK, Racie T, Rajeev KG, Rohl I, Toudjarska I, Wang G, Wuschko S, Bumcrot D, Koteliansky V, Limmer S, Manoharan M, Vornlocher HP (2004) Therapeutic silencing of an endogenous gene by systemic administration of modified siRNAs. Nature 432(7014):173–178. https://doi.org/10.1038/nature03121
Tomiyama K, Maeda R, Urakawa I, Yamazaki Y, Tanaka T, Ito S, Nabeshima Y, Tomita T, Odori S, Hosoda K (2010) Relevant use of klotho in FGF19 subfamily signaling system in vivo. Proc Natl Acad Sci U S A 107(4):1666–1671. https://doi.org/10.1073/pnas.0913986107
Turner N, Grose R (2010) Fibroblast growth factor signalling: from development to cancer. Nat Rev Cancer 10(2):116–129. https://doi.org/10.1038/nrc2780
Uriarte I, Fernandez-Barrena MG, Monte MJ, Latasa MU, Chang HC, Carotti S, Vespasiani-Gentilucci U, Morini S, Vicente E, Concepcion AR, Medina JF, Marin JJ, Berasain C, Prieto J, Avila MA (2013) Identification of fibroblast growth factor 15 as a novel mediator of liver regeneration and its application in the prevention of post-resection liver failure in mice. Gut 62(6):899–910. https://doi.org/10.1136/gutjnl-2012-302945
Uriarte I, Latasa MU, Carotti S, Fernandez-Barrena MG, Garcia-Irigoyen O, Elizalde M, Urtasun R, Vespasiani-Gentilucci U, Morini S, de Mingo A, Mari M, Corrales FJ, Prieto J, Berasain C, Avila MA (2015) Ileal FGF15 contributes to fibrosis-associated hepatocellular carcinoma development. Int J Cancer 136(10):2469–2475. https://doi.org/10.1002/ijc.29287
Vergnes L, Lee JM, Chin RG, Auwerx J, Reue K (2013) Diet1 functions in the FGF15/19 enterohepatic signaling axis to modulate bile acid and lipid levels. Cell Metab 17(6):916–928. https://doi.org/10.1016/j.cmet.2013.04.007
Veteläinen R, van Vliet AK, van Gulik TM (2007) Severe steatosis increases hepatocellular injury and impairs liver regeneration in a rat model of partial hepatectomy. Ann Surg 245(1):44–50. https://doi.org/10.1097/01.sla.0000225253.84501.0e
Wang J, Stockton DW, Ittmann M (2004) The fibroblast growth factor receptor-4 Arg388 allele is associated with prostate cancer initiation and progression. Clin Cancer Res 10(18):6169–6178. https://doi.org/10.1158/1078-0432.CCR-04-0408
Wu X, Li Y (2009) Role of FGF19 induced FGFR4 activation in the regulation of glucose homeostasis. Aging 1(12):1023–1027. https://doi.org/10.18632/aging.100108
Yamauchia H, Okada T, Nakayama H, Doi K (2003) Impaired liver regeneration after partial hepatectomy in db/db mice. Exp Toxicol Pathol 54(4):281–286. https://doi.org/10.1078/0940-2993-00265
Yu C, Wang F, Kan M, Jin C, Jones RB, Weinstein M, Deng CX, Mckeehan WL (2000) Elevated cholesterol metabolism and bile acid synthesis in mice lacking membrane tyrosine kinase receptor FGFR4. J Biol Chem 275(20):15482–15489. https://doi.org/10.1074/jbc.275.20.15482
Yu C, Wang F, Jin C, Wu X, Chan WK, Mckeehan WL (2003) Increased carbon tetrachloride-induced liver injury and fibrosis in FGFR4-deficient mice. Am J Pathol 161:2003–2010
Yu S, Matsusue K, Kashireddy P, Cao WQ, Yeldandi V, Yeldandi AV, Rao MS, Gonzalez FJ, Reddy JK (2003) Adipocyte-specific gene expression and adipogenic steatosis in the mouse liver due to peroxisome proliferator-activated receptor gamma1 (PPARgamma1) overexpression. J Biol Chem 278(1):498–505. https://doi.org/10.1074/jbc.M210062200
Zhang L, Wang YD, Chen WD, Wang X, Lou G, Liu N, Lin M, Forman BM, Huang W (2012) Promotion of liver regeneration/repair by farnesoid X receptor in both liver and intestine in mice. Hepatology 56(6):2336–2343. https://doi.org/10.1002/hep.25905
Funding
This work was supported by the Science and Technology Planning Project of Guangdong Province (2013B051000020, 2013B040200019, and 2014A030304017), the Science and Technology Planning Project of Guangzhou (2014Y2–00114), the National High Technology Research and Development Program of China (863 Program) (2012AA021007 and 2012AA021008), the National Natural Science Foundation of China (81373156 and 81471583), the Special Fund for Science Research by Ministry of Health (201002004 and 201302009), the Key Clinical Specialty Construction Project of National Health and Family Planning Commission of the People’s Republic of China, the Science and Technology Planning Key Clinical Project of Guangdong Province (2011A030400005), and the Guangdong Provincial Key Laboratory Construction Projection on Organ Donation and Transplant Immunology (2013A061401007).
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Li, Q., Zhao, Q., Zhang, C. et al. The ileal FGF15/19 to hepatic FGFR4 axis regulates liver regeneration after partial hepatectomy in mice. J Physiol Biochem 74, 247–260 (2018). https://doi.org/10.1007/s13105-018-0610-8
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DOI: https://doi.org/10.1007/s13105-018-0610-8