Abstract
The liver is a highly differentiated organ with a central role in metabolism, detoxification and systemic homeostasis. To perform its multiple tasks, liver parenchymal cells, the hepatocytes, express a large complement of enabling genes defining their complex phenotype. This phenotype is progressively acquired during fetal development and needs to be maintained in adulthood to guarantee the individual’s survival. Upon injury or loss of functional mass, the liver displays an extraordinary regenerative response, mainly based on the proliferation of hepatocytes which otherwise are long-lived quiescent cells. Increasing observations suggest that loss of hepatocellular differentiation and quiescence underlie liver malfunction in chronic liver disease and pave the way for hepatocellular carcinoma development. Here, we briefly review the essential mechanisms leading to the acquisition of liver maturity. We also identify the key molecular factors involved in the preservation of hepatocellular homeostasis and finally discuss potential strategies to preserve liver identity and function.
Similar content being viewed by others
References
Treyer A, Müsch A (2013) Hepatocyte polarity. Compr Physiol 3:243–287. doi:10.1002/cphy.c120009
Torre C, Perret C, Colnot S (2010) Molecular determinants of liver zonation. Prog Mol Biol Transl Sci 97:127–150. doi:10.1016/B978-0-12-385233-5.00005-2
Costa RH, Kalinichenko VV, Holterman A-XL, Wang X (2003) Transcription factors in liver development, differentiation, and regeneration. Hepatology 38:1331–1347. doi:10.1016/j.hep.2003.09.034
Zaret KS, Watts J, Xu J et al (2008) Pioneer factors, genetic competence, and inductive signaling: programming liver and pancreas progenitors from the endoderm. Cold Spring Harb Symp Quant Biol 73:119–126. doi:10.1101/sqb.2008.73.040
Lemaigre FP (2009) Mechanisms of liver development: concepts for understanding liver disorders and design of novel therapies. Gastroenterology 137:62–79. doi:10.1053/j.gastro.2009.03.035
Si-Tayeb K, Lemaigre FP, Duncan SA (2010) Organogenesis and development of the liver. Dev Cell 18:175–189. doi:10.1016/j.devcel.2010.01.011
Zong Y, Stanger BZ (2012) Molecular mechanisms of liver and bile duct development. Wiley Interdiscip Rev Dev Biol 1:643–655. doi:10.1002/wdev.47
Avila MA, Berasain C, Torres L et al (2000) Reduced mRNA abundance of the main enzymes involved in methionine metabolism in human liver cirrhosis and hepatocellular carcinoma. J Hepatol 33:907–914
Lerose R, Molinari R, Rocchi E et al (2001) Prognostic features and survival of hepatocellular carcinoma in Italy: impact of stage of disease. Eur J Cancer 37:239–245
Berasain C, Herrero J-I, García-Trevijano ER et al (2003) Expression of Wilms’ tumor suppressor in the liver with cirrhosis: relation to hepatocyte nuclear factor 4 and hepatocellular function. Hepatology 38:148–157. doi:10.1053/jhep.2003.50269
Lee J-S, Heo J, Libbrecht L et al (2006) A novel prognostic subtype of human hepatocellular carcinoma derived from hepatic progenitor cells. Nat Med 12:410–416. doi:10.1038/nm1377
Hoshida Y, Villanueva A, Kobayashi M et al (2008) Gene expression in fixed tissues and outcome in hepatocellular carcinoma. N Engl J Med 359:1995–2004. doi:10.1056/NEJMoa0804525
Becker D, Sfakianakis I, Krupp M et al (2012) Genetic signatures shared in embryonic liver development and liver cancer define prognostically relevant subgroups in HCC. Mol Cancer 11:55. doi:10.1186/1476-4598-11-55
Behnke M, Reimers M, Fisher R (2012) The expression of embryonic liver development genes in hepatitis C induced cirrhosis and hepatocellular carcinoma. Cancers 4:945–968. doi:10.3390/cancers4030945
Bruix J, Gores GJ, Mazzaferro V (2014) Hepatocellular carcinoma: clinical frontiers and perspectives. Gut 63:844–855. doi:10.1136/gutjnl-2013-306627
Blachier M, Leleu H, Peck-Radosavljevic M et al (2013) The burden of liver disease in Europe: a review of available epidemiological data. J Hepatol 58:593–608. doi:10.1016/j.jhep.2012.12.005
Michalopoulos GK (2013) Principles of liver regeneration and growth homeostasis. Compr Physiol 3:485–513. doi:10.1002/cphy.c120014
Michalopoulos GK, DeFrances MC (1997) Liver regeneration. Science 276:60–66
Grisham JW (1962) A morphologic study of deoxyribonucleic acid synthesis and cell proliferation in regenerating rat liver; autoradiography with thymidine-H3. Cancer Res 22:842–849
Gentric G, Desdouets C (2014) Polyploidization in liver tissue. Am J Pathol 184:322–331. doi:10.1016/j.ajpath.2013.06.035
Gentric G, Maillet V, Paradis V et al (2015) Oxidative stress promotes pathologic polyploidization in nonalcoholic fatty liver disease. J Clin Invest 125:981–992. doi:10.1172/JCI73957
Duncan AW (2013) Aneuploidy, polyploidy and ploidy reversal in the liver. Semin Cell Dev Biol 24:347–356. doi:10.1016/j.semcdb.2013.01.003
Taub R (2004) Liver regeneration: from myth to mechanism. Nat Rev Mol Cell Biol 5:836–847. doi:10.1038/nrm1489
Michalopoulos GK (2007) Liver regeneration. J Cell Physiol 213:286–300. doi:10.1002/jcp.21172
Michalopoulos GK (2010) Liver regeneration after partial hepatectomy: critical analysis of mechanistic dilemmas. Am J Pathol 176:2–13. doi:10.2353/ajpath.2010.090675
Avila MA, Berasain C, Sangro B, Prieto J (2006) New therapies for hepatocellular carcinoma. Oncogene 25:3866–3884. doi:10.1038/sj.onc.1209550
Breuhahn K, Schirmacher P (2010) Signaling networks in human hepatocarcinogenesis—novel aspects and therapeutic options. Prog Mol Biol Transl Sci 97:251–277. doi:10.1016/B978-0-12-385233-5.00009-X
Hernandez-Gea V, Toffanin S, Friedman SL, Llovet JM (2013) Role of the microenvironment in the pathogenesis and treatment of hepatocellular carcinoma. Gastroenterology 144:512–527. doi:10.1053/j.gastro.2013.01.002
Gualdi R, Bossard P, Zheng M et al (1996) Hepatic specification of the gut endoderm in vitro: cell signaling and transcriptional control. Genes Dev 10:1670–1682
Lade AG, Monga SPS (2011) Beta-catenin signaling in hepatic development and progenitors: which way does the WNT blow? Dev Dyn 240:486–500. doi:10.1002/dvdy.22522
Nagaoka M, Duncan SA (2010) Transcriptional control of hepatocyte differentiation. Prog Mol Biol Transl Sci 97:79–101. doi:10.1016/B978-0-12-385233-5.00003-9
Xu C-R, Cole PA, Meyers DJ et al (2011) Chromatin “prepattern” and histone modifiers in a fate choice for liver and pancreas. Science 332:963–966. doi:10.1126/science.1202845
Lee CS, Friedman JR, Fulmer JT, Kaestner KH (2005) The initiation of liver development is dependent on Foxa transcription factors. Nature 435:944–947. doi:10.1038/nature03649
Li Z, White P, Tuteja G et al (2009) Foxa1 and Foxa2 regulate bile duct development in mice. J Clin Invest 119:1537–1545. doi:10.1172/JCI38201
Le Lay J, Kaestner KH (2010) The Fox genes in the liver: from organogenesis to functional integration. Physiol Rev 90:1–22. doi:10.1152/physrev.00018.2009
Lokmane L, Haumaitre C, Garcia-Villalba P et al (2008) Crucial role of vHNF1 in vertebrate hepatic specification. Development 135:2777–2786. doi:10.1242/dev.023010
Zhang W, Yatskievych TA, Baker RK, Antin PB (2004) Regulation of Hex gene expression and initial stages of avian hepatogenesis by Bmp and Fgf signaling. Dev Biol 268:312–326. doi:10.1016/j.ydbio.2004.01.019
Hunter MP, Wilson CM, Jiang X et al (2007) The homeobox gene Hhex is essential for proper hepatoblast differentiation and bile duct morphogenesis. Dev Biol 308:355–367. doi:10.1016/j.ydbio.2007.05.028
Sosa-Pineda B, Wigle JT, Oliver G (2000) Hepatocyte migration during liver development requires Prox1. Nat Genet 25:254–255. doi:10.1038/76996
Lüdtke TH-W, Christoffels VM, Petry M, Kispert A (2009) Tbx3 promotes liver bud expansion during mouse development by suppression of cholangiocyte differentiation. Hepatology 49:969–978. doi:10.1002/hep.22700
Margagliotti S, Clotman F, Pierreux CE et al (2007) The Onecut transcription factors HNF-6/OC-1 and OC-2 regulate early liver expansion by controlling hepatoblast migration. Dev Biol 311:579–589. doi:10.1016/j.ydbio.2007.09.013
Matsumoto K, Miki R, Nakayama M et al (2008) Wnt9a secreted from the walls of hepatic sinusoids is essential for morphogenesis, proliferation, and glycogen accumulation of chick hepatic epithelium. Dev Biol 319:234–247. doi:10.1016/j.ydbio.2008.04.021
Tan X, Yuan Y, Zeng G et al (2008) Beta-catenin deletion in hepatoblasts disrupts hepatic morphogenesis and survival during mouse development. Hepatology 47:1667–1679. doi:10.1002/hep.22225
Suzuki A, Iwama A, Miyashita H et al (2003) Role for growth factors and extracellular matrix in controlling differentiation of prospectively isolated hepatic stem cells. Development 130:2513–2524
Takayama K, Kawabata K, Nagamoto Y et al (2014) CCAAT/enhancer binding protein-mediated regulation of TGFβ receptor 2 expression determines the hepatoblast fate decision. Development 141:91–100. doi:10.1242/dev.103168
Kamiya A, Kinoshita T, Ito Y et al (1999) Fetal liver development requires a paracrine action of oncostatin M through the gp130 signal transducer. EMBO J 18:2127–2136. doi:10.1093/emboj/18.8.2127
Ito Y, Matsui T, Kamiya A et al (2000) Retroviral gene transfer of signaling molecules into murine fetal hepatocytes defines distinct roles for the STAT3 and ras pathways during hepatic development. Hepatology 32:1370–1376. doi:10.1053/jhep.2000.19815
Santamaría M, Pardo-Saganta A, Alvarez-Asiain L et al (2013) Nuclear α1-antichymotrypsin promotes chromatin condensation and inhibits proliferation of human hepatocellular carcinoma cells. Gastroenterology 144(818–828):e4. doi:10.1053/j.gastro.2012.12.029
Suzuki A, Sekiya S, Büscher D et al (2008) Tbx3 controls the fate of hepatic progenitor cells in liver development by suppressing p19ARF expression. Development 135:1589–1595. doi:10.1242/dev.016634
Li J, Ning G, Duncan SA (2000) Mammalian hepatocyte differentiation requires the transcription factor HNF-4alpha. Genes Dev 14:464–474
Yamasaki H, Sada A, Iwata T et al (2006) Suppression of C/EBPalpha expression in periportal hepatoblasts may stimulate biliary cell differentiation through increased Hnf6 and Hnf1b expression. Development 133:4233–4243. doi:10.1242/dev.02591
Clotman F, Lannoy VJ, Reber M et al (2002) The onecut transcription factor HNF6 is required for normal development of the biliary tract. Development 129:1819–1828
Schrem H, Klempnauer J, Borlak J (2002) Liver-enriched transcription factors in liver function and development. Part I: the hepatocyte nuclear factor network and liver-specific gene expression. Pharmacol Rev 54:129–158
Kyrmizi I, Hatzis P, Katrakili N et al (2006) Plasticity and expanding complexity of the hepatic transcription factor network during liver development. Genes Dev 20:2293–2305. doi:10.1101/gad.390906
Stein S, Schoonjans K (2014) Molecular basis for the regulation of the nuclear receptor LRH-1. Curr Opin Cell Biol 33C:26–34. doi:10.1016/j.ceb.2014.10.007
Kamiya A, Inoue Y, Gonzalez FJ (2003) Role of the hepatocyte nuclear factor 4alpha in control of the pregnane X receptor during fetal liver development. Hepatology 37:1375–1384. doi:10.1053/jhep.2003.50212
Alder O, Cullum R, Lee S et al (2014) Hippo signaling influences HNF4A and FOXA2 enhancer switching during hepatocyte differentiation. Cell Rep 9:261–271. doi:10.1016/j.celrep.2014.08.046
Tatarakis A, Margaritis T, Martinez-Jimenez CP et al (2008) Dominant and redundant functions of TFIID involved in the regulation of hepatic genes. Mol Cell 31:531–543. doi:10.1016/j.molcel.2008.07.013
Alpern D, Langer D, Ballester B et al (2014) TAF4, a subunit of transcription factor II D, directs promoter occupancy of nuclear receptor HNF4A during post-natal hepatocyte differentiation. Elife 3:e03613. doi:10.7554/eLife.03613
Wang ND, Finegold MJ, Bradley A et al (1995) Impaired energy homeostasis in C/EBP alpha knockout mice. Science 269:1108–1112
Flodby P, Barlow C, Kylefjord H et al (1996) Increased hepatic cell proliferation and lung abnormalities in mice deficient in CCAAT/enhancer binding protein alpha. J Biol Chem 271:24753–24760
Johnson PF (2005) Molecular stop signs: regulation of cell-cycle arrest by C/EBP transcription factors. J Cell Sci 118:2545–2555. doi:10.1242/jcs.02459
Locker J, Ghosh D, Luc P-V, Zheng J (2002) Definition and prediction of the full range of transcription factor binding sites–the hepatocyte nuclear factor 1 dimeric site. Nucleic Acids Res 30:3809–3817
Odom DT, Zizlsperger N, Gordon DB et al (2004) Control of pancreas and liver gene expression by HNF transcription factors. Science 303:1378–1381. doi:10.1126/science.1089769
Coffinier C, Gresh L, Fiette L et al (2002) Bile system morphogenesis defects and liver dysfunction upon targeted deletion of HNF1beta. Development 129:1829–1838
Pontoglio M, Barra J, Hadchouel M et al (1996) Hepatocyte nuclear factor 1 inactivation results in hepatic dysfunction, phenylketonuria, and renal Fanconi syndrome. Cell 84:575–585
Lee YH, Sauer B, Gonzalez FJ (1998) Laron dwarfism and non-insulin-dependent diabetes mellitus in the Hnf-1alpha knockout mouse. Mol Cell Biol 18:3059–3068
Bochkis IM, Rubins NE, White P et al (2008) Hepatocyte-specific ablation of Foxa2 alters bile acid homeostasis and results in endoplasmic reticulum stress. Nat Med 14:828–836. doi:10.1038/nm.1853
Parviz F, Matullo C, Garrison WD et al (2003) Hepatocyte nuclear factor 4alpha controls the development of a hepatic epithelium and liver morphogenesis. Nat Genet 34:292–296. doi:10.1038/ng1175
Späth GF, Weiss MC (1998) Hepatocyte nuclear factor 4 provokes expression of epithelial marker genes, acting as a morphogen in dedifferentiated hepatoma cells. J Cell Biol 140:935–946
Hayhurst GP, Lee YH, Lambert G et al (2001) Hepatocyte nuclear factor 4alpha (nuclear receptor 2A1) is essential for maintenance of hepatic gene expression and lipid homeostasis. Mol Cell Biol 21:1393–1403. doi:10.1128/MCB.21.4.1393-1403.2001
Martinez-Jimenez CP, Kyrmizi I, Cardot P et al (2010) Hepatocyte nuclear factor 4alpha coordinates a transcription factor network regulating hepatic fatty acid metabolism. Mol Cell Biol 30:565–577. doi:10.1128/MCB.00927-09
Santangelo L, Marchetti A, Cicchini C et al (2011) The stable repression of mesenchymal program is required for hepatocyte identity: a novel role for hepatocyte nuclear factor 4α. Hepatology 53:2063–2074. doi:10.1002/hep.24280
Garibaldi F, Cicchini C, Conigliaro A et al (2012) An epistatic mini-circuitry between the transcription factors Snail and HNF4α controls liver stem cell and hepatocyte features exhorting opposite regulation on stemness-inhibiting microRNAs. Cell Death Differ 19:937–946. doi:10.1038/cdd.2011.175
Sladek FM, Zhong WM, Lai E, Darnell JE (1990) Liver-enriched transcription factor HNF-4 is a novel member of the steroid hormone receptor superfamily. Genes Dev 4:2353–2365
Torres-Padilla ME, Fougère-Deschatrette C, Weiss MC (2001) Expression of HNF4alpha isoforms in mouse liver development is regulated by sequential promoter usage and constitutive 3′ end splicing. Mech Dev 109:183–193
Nakhei H, Lingott A, Lemm I, Ryffel GU (1998) An alternative splice variant of the tissue specific transcription factor HNF4alpha predominates in undifferentiated murine cell types. Nucleic Acids Res 26:497–504
Sladek FM, Ruse MD, Nepomuceno L et al (1999) Modulation of transcriptional activation and coactivator interaction by a splicing variation in the F domain of nuclear receptor hepatocyte nuclear factor 4alpha1. Mol Cell Biol 19:6509–6522
Wang JC, Stafford JM, Granner DK (1998) SRC-1 and GRIP1 coactivate transcription with hepatocyte nuclear factor 4. J Biol Chem 273:30847–30850
Yoon JC, Puigserver P, Chen G et al (2001) Control of hepatic gluconeogenesis through the transcriptional coactivator PGC-1. Nature 413:131–138. doi:10.1038/35093050
Torres-Padilla ME, Sladek FM, Weiss MC (2002) Developmentally regulated N-terminal variants of the nuclear receptor hepatocyte nuclear factor 4alpha mediate multiple interactions through coactivator and corepressor-histone deacetylase complexes. J Biol Chem 277:44677–44687. doi:10.1074/jbc.M207545200
Briançon N, Weiss MC (2006) In vivo role of the HNF4alpha AF-1 activation domain revealed by exon swapping. EMBO J 25:1253–1262. doi:10.1038/sj.emboj.7601021
Tanaka T, Jiang S, Hotta H et al (2006) Dysregulated expression of P1 and P2 promoter-driven hepatocyte nuclear factor-4alpha in the pathogenesis of human cancer. J Pathol 208:662–672. doi:10.1002/path.1928
Chiba H, Itoh T, Satohisa S et al (2005) Activation of p21CIP1/WAF1 gene expression and inhibition of cell proliferation by overexpression of hepatocyte nuclear factor-4alpha. Exp Cell Res 302:11–21. doi:10.1016/j.yexcr.2004.08.014
Locker J (2011) Transcriptional control of hepatocyte differentiation. doi:10.1007/978-1-4419-7107-4_14
Perugorría MJ, Castillo J, Latasa MU et al (2009) Wilms’ tumor 1 gene expression in hepatocellular carcinoma promotes cell dedifferentiation and resistance to chemotherapy. Cancer Res 69:1358–1367. doi:10.1158/0008-5472.CAN-08-2545
Tremosini S, Forner A, Boix L et al (2012) Prospective validation of an immunohistochemical panel (glypican 3, heat shock protein 70 and glutamine synthetase) in liver biopsies for diagnosis of very early hepatocellular carcinoma. Gut 61:1481–1487. doi:10.1136/gutjnl-2011-301862
Liu X, Wang SK, Zhang K et al (2015) Expression of glypican 3 enriches hepatocellular carcinoma development-related genes and associates with carcinogenesis in cirrhotic livers. Carcinogenesis 36:232–242. doi:10.1093/carcin/bgu245
Martínez-Chantar ML, García-Trevijano ER, Latasa MU et al (2003) Methionine adenosyltransferase II beta subunit gene expression provides a proliferative advantage in human hepatoma. Gastroenterology 124:940–948. doi:10.1053/gast.2003.50151
Filmus J, Capurro M (2013) Glypican-3: a marker and a therapeutic target in hepatocellular carcinoma. FEBS J 280:2471–2476. doi:10.1111/febs.12126
Spear BT, Jin L, Ramasamy S, Dobierzewska A (2006) Transcriptional control in the mammalian liver: liver development, perinatal repression, and zonal gene regulation. Cell Mol Life Sci 63:2922–2938. doi:10.1007/s00018-006-6258-5
Morford LA, Davis C, Jin L et al (2007) The oncofetal gene glypican 3 is regulated in the postnatal liver by zinc fingers and homeoboxes 2 and in the regenerating liver by alpha-fetoprotein regulator 2. Hepatology 46:1541–1547. doi:10.1002/hep.21825
Yue X, Zhang Z, Liang X et al (2012) Zinc fingers and homeoboxes 2 inhibits hepatocellular carcinoma cell proliferation and represses expression of Cyclins A and E. Gastroenterology 142(1559–70):e2. doi:10.1053/j.gastro.2012.02.049
Luan F, Liu P, Ma H et al (2014) Reduced nucleic ZHX2 involves in oncogenic activation of glypican 3 in human hepatocellular carcinoma. Int J Biochem Cell Biol 55:129–135. doi:10.1016/j.biocel.2014.08.021
Colnot S, Perret C (2011) Liver zonation. In: Monga SPS (ed) Molecular pathology of liver diseases. Chapter 2. Springer, pp 7–16. doi: 10.1007/978-1-4419-7107-4_2
Jungermann K, Kietzmann T (1996) Zonation of parenchymal and nonparenchymal metabolism in liver. Annu Rev Nutr 16:179–203. doi:10.1146/annurev.nu.16.070196.001143
Gebhardt R, Matz-Soja M (2014) Liver zonation: novel aspects of its regulation and its impact on homeostasis. World J Gastroenterol 20:8491–8504. doi:10.3748/wjg.v20.i26.8491
Schleicher J, Tokarski C, Marbach E et al (2015) Zonation of hepatic fatty acid metabolism - The diversity of its regulation and the benefit of modeling. Biochim Biophys Acta. doi:10.1016/j.bbalip.2015.02.004
Torre C, Perret C, Colnot S (2011) Transcription dynamics in a physiological process: Î2-Catenin signaling directs liver metabolic zonation. Int J Biochem Cell Biol 43:271–278. doi:10.1016/j.biocel.2009.11.004
Gebhardt R, Hovhannisyan A (2010) Organ patterning in the adult stage: the role of Wnt/beta-catenin signaling in liver zonation and beyond. Dev Dyn 239:45–55. doi:10.1002/dvdy.22041
Notenboom RG, Moorman AF, Lamers WH (1997) Developmental appearance of ammonia-metabolizing enzymes in prenatal murine liver. Microsc Res Tech 39:413–423. doi:10.1002/(SICI)1097-0029(19971201)39:5<413:AID-JEMT4>3.0.CO;2-H
Braeuning A, Ittrich C, Köhle C et al (2006) Differential gene expression in periportal and perivenous mouse hepatocytes. FEBS J 273:5051–5061. doi:10.1111/j.1742-4658.2006.05503.x
Berasain C, Avila MA (2014) Deciphering liver zonation: new insights into the β-catenin, Tcf4, and HNF4α triad. Hepatology 59:2080–2082. doi:10.1002/hep.27000
Benhamouche S, Decaens T, Godard C et al (2006) Apc tumor suppressor gene is the “zonation-keeper” of mouse liver. Dev Cell 10:759–770. doi:10.1016/j.devcel.2006.03.015
Yang J, Mowry LE, Nejak-Bowen KN et al (2014) β-catenin signaling in murine liver zonation and regeneration: a Wnt-Wnt situation! Hepatology 60:964–976. doi:10.1002/hep.27082
Lindros KO, Oinonen T, Issakainen J et al (1997) Zonal distribution of transcripts of four hepatic transcription factors in the mature rat liver. Cell Biol Toxicol 13:257–262
Stanulović VS, Kyrmizi I, Kruithof-de Julio M et al (2007) Hepatic HNF4alpha deficiency induces periportal expression of glutamine synthetase and other pericentral enzymes. Hepatology 45:433–444. doi:10.1002/hep.21456
Colletti M, Cicchini C, Conigliaro A et al (2009) Convergence of Wnt signaling on the HNF4alpha-driven transcription in controlling liver zonation. Gastroenterology 137:660–672. doi:10.1053/j.gastro.2009.05.038
Gougelet A, Torre C, Veber P et al (2014) T-cell factor 4 and β-catenin chromatin occupancies pattern zonal liver metabolism in mice. Hepatology 59:2344–2357. doi:10.1002/hep.26924
Macdonald RA (1961) “Lifespan” of liver cells. Autoradio-graphic study using tritiated thymidine in normal, cirrhotic, and partially hepatectomized rats. Arch Intern Med 107:335–343
Terpstra OT, Malt RA, Bucher NL (1979) Negligible role of adrenal hormones in regulation of DNA synthesis in livers of partially hepatectomized rats. Proc Soc Exp Biol Med 161:326–331
Zajicek G, Oren R, Weinreb M (1985) The streaming liver. Liver 5:293–300
Furuyama K, Kawaguchi Y, Akiyama H et al (2011) Continuous cell supply from a Sox9-expressing progenitor zone in adult liver, exocrine pancreas and intestine. Nat Genet 43:34–41. doi:10.1038/ng.722
Stanger BZ (2015) Cellular homeostasis and repair in the Mammalian liver. Annu Rev Physiol 77:179–200. doi:10.1146/annurev-physiol-021113-170255
Suzuki A (2015) MBSJ MCC Young Scientist Award 2012 Liver regeneration: a unique and flexible reaction depending on the type of injury. Genes Cells 20:77–84. doi:10.1111/gtc.12200
Diehl AM, Chute J (2013) Underlying potential: cellular and molecular determinants of adult liver repair. J Clin Invest 123:1858–1860. doi:10.1172/JCI69966
Williams MJ, Clouston AD, Forbes SJ (2014) Links between hepatic fibrosis, ductular reaction, and progenitor cell expansion. Gastroenterology 146:349–356. doi:10.1053/j.gastro.2013.11.034
Rashid T, Takebe T, Nakauchi H (2015) Novel strategies for liver therapy using stem cells. Gut 64:1–4. doi:10.1136/gutjnl-2014-307480
Tarlow BD, Pelz C, Naugler WE et al (2014) Bipotential adult liver progenitors are derived from chronically injured mature hepatocytes. Cell Stem Cell 15:605–618. doi:10.1016/j.stem.2014.09.008
Schaub JR, Malato Y, Gormond C, Willenbring H (2014) Evidence against a stem cell origin of new hepatocytes in a common mouse model of chronic liver injury. Cell Rep 8:933–939. doi:10.1016/j.celrep.2014.07.003
Boulter L, Lu W-Y, Forbes SJ (2013) Differentiation of progenitors in the liver: a matter of local choice. J Clin Invest 123:1867–1873. doi:10.1172/JCI66026
Huch M, Dorrell C, Boj SF et al (2013) In vitro expansion of single Lgr5 + liver stem cells induced by Wnt-driven regeneration. Nature 494:247–250. doi:10.1038/nature11826
Doignon I, Julien B, Serrière-Lanneau V et al (2011) Immediate neuroendocrine signaling after partial hepatectomy through acute portal hyperpressure and cholestasis. J Hepatol 54:481–488. doi:10.1016/j.jhep.2010.07.012
Avila MA (2011) Long distance calling for liver regeneration: identification of neuroendocrine signalling pathways activated after partial hepatectomy. J Hepatol 54:403–405. doi:10.1016/j.jhep.2010.08.009
Mortensen KE, Revhaug A (2011) Liver regeneration in surgical animal models—a historical perspective and clinical implications. Eur Surg Res 46:1–18. doi:10.1159/000321361
Fausto N, Campbell JS, Riehle KJ (2012) Liver regeneration. J Hepatol 57:692–694. doi:10.1016/j.jhep.2012.04.016
Fausto N, Campbell JS, Riehle KJ (2006) Liver regeneration. Hepatology 43:S45–S53. doi:10.1002/hep.20969
García-Trevijano ER, Martínez-Chantar ML, Latasa MU et al (2002) NO sensitizes rat hepatocytes to proliferation by modifying s-adenosylmethionine levels. Gastroenterology 122:1355–1363
Huh C-G, Factor VM, Sánchez A et al (2004) Hepatocyte growth factor/c-met signaling pathway is required for efficient liver regeneration and repair. Proc Natl Acad Sci USA 101:4477–4482. doi:10.1073/pnas.0306068101
Berasain C, García-Trevijano ER, Castillo J et al (2005) Amphiregulin: an early trigger of liver regeneration in mice. Gastroenterology 128:424–432
Campbell JS, Riehle KJ, Brooling JT et al (2006) Proinflammatory cytokine production in liver regeneration is Myd88-dependent, but independent of Cd14, Tlr2, and Tlr4. J Immunol 176:2522–2528
DeAngelis RA, Markiewski MM, Lambris JD (2006) Liver regeneration: a link to inflammation through complement. Adv Exp Med Biol 586:17–34. doi:10.1007/0-387-34134-X_2
Böhm F, Köhler UA, Speicher T, Werner S (2010) Regulation of liver regeneration by growth factors and cytokines. EMBO Mol Med 2:294–305. doi:10.1002/emmm.201000085
Fernández-Barrena MG, Monte MJ, Latasa MU et al (2012) Lack of Abcc3 expression impairs bile-acid induced liver growth and delays hepatic regeneration after partial hepatectomy in mice. J Hepatol 56:367–373. doi:10.1016/j.jhep.2011.05.031
Uriarte I, Fernández-Barrena MG, Monte MJ et al (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 62:899–910. doi:10.1136/gutjnl-2012-302945
Fan M, Wang X, Xu G et al (2015) Bile acid signaling and liver regeneration. Biochim Biophys Acta 1849:196–200. doi:10.1016/j.bbagrm.2014.05.021
Gilgenkrantz H, Tordjmann T (2015) Bile acids and FGF receptors: orchestrators of optimal liver regeneration. Gut. doi:10.1136/gutjnl-2014-308746
Vacca M, Degirolamo C, Massafra V et al (2013) Nuclear receptors in regenerating liver and hepatocellular carcinoma. Mol Cell Endocrinol 368:108–119. doi:10.1016/j.mce.2012.06.025
Huang W, Ma K, Zhang J et al (2006) Nuclear receptor-dependent bile acid signaling is required for normal liver regeneration. Science 312:233–236. doi:10.1126/science.1121435
Pibiri M, Ledda-Columbano GM, Cossu C et al (2001) Cyclin D1 is an early target in hepatocyte proliferation induced by thyroid hormone (T3). FASEB J 15:1006–1013
Huang J, Rudnick DA (2014) Elucidating the metabolic regulation of liver regeneration. Am J Pathol 184:309–321. doi:10.1016/j.ajpath.2013.04.034
Flodby P, Antonson P, Barlow C et al (1993) Differential patterns of expression of three C/EBP isoforms, HNF-1, and HNF-4 after partial hepatectomy in rats. Exp Cell Res 208:248–256. doi:10.1006/excr.1993.1244
Greenbaum LE, Cressman DE, Haber BA, Taub R (1995) Coexistence of C/EBP alpha, beta, growth-induced proteins and DNA synthesis in hepatocytes during liver regeneration. Implications for maintenance of the differentiated state during liver growth. J Clin Invest 96:1351–1365. doi:10.1172/JCI118170
Qian X, Samadani U, Porcella A, Costa RH (1995) Decreased expression of hepatocyte nuclear factor 3 alpha during the acute-phase response influences transthyretin gene transcription. Mol Cell Biol 15:1364–1376
Tan Y, Yoshida Y, Hughes DE, Costa RH (2006) Increased expression of hepatocyte nuclear factor 6 stimulates hepatocyte proliferation during mouse liver regeneration. Gastroenterology 130:1283–1300. doi:10.1053/j.gastro.2006.01.010
Weymann A, Hartman E, Gazit V et al (2009) p21 is required for dextrose-mediated inhibition of mouse liver regeneration. Hepatology 50:207–215. doi:10.1002/hep.22979
Croniger C, Trus M, Lysek-Stupp K et al (1997) Role of the isoforms of CCAAT/enhancer-binding protein in the initiation of phosphoenolpyruvate carboxykinase (GTP) gene transcription at birth. J Biol Chem 272:26306–26312
Greenbaum LE, Li W, Cressman DE et al (1998) CCAAT enhancer- binding protein beta is required for normal hepatocyte proliferation in mice after partial hepatectomy. J Clin Invest 102:996–1007. doi:10.1172/JCI3135
Bonzo JA, Ferry CH, Matsubara T et al (2012) Suppression of hepatocyte proliferation by hepatocyte nuclear factor 4α in adult mice. J Biol Chem 287:7345–7356. doi:10.1074/jbc.M111.334599
Walesky C, Gunewardena S, Terwilliger EF et al (2013) Hepatocyte-specific deletion of hepatocyte nuclear factor-4α in adult mice results in increased hepatocyte proliferation. Am J Physiol Gastrointest Liver Physiol 304:G26–G37. doi:10.1152/ajpgi.00064.2012
Bolotin E, Liao H, Ta TC et al (2010) Integrated approach for the identification of human hepatocyte nuclear factor 4 alpha target genes using protein binding microarrays. Hepatology 51:642–653. doi:10.1002/hep.23357
Lazarevich NL, Cheremnova OA, Varga EV et al (2004) Progression of HCC in mice is associated with a downregulation in the expression of hepatocyte nuclear factors. Hepatology 39:1038–1047. doi:10.1002/hep.20155
Tan X, Behari J, Cieply B et al (2006) Conditional deletion of beta-catenin reveals its role in liver growth and regeneration. Gastroenterology 131:1561–1572. doi:10.1053/j.gastro.2006.08.042
Hanse EA, Mashek DG, Becker JR et al (2012) Cyclin D1 inhibits hepatic lipogenesis via repression of carbohydrate response element binding protein and hepatocyte nuclear factor 4α. Cell Cycle 11:2681–2690. doi:10.4161/cc.21019
Grijalva JL, Huizenga M, Mueller K et al (2014) Dynamic alterations in Hippo signaling pathway and YAP activation during liver regeneration. Am J Physiol Gastrointest Liver Physiol 307:G196–G204. doi:10.1152/ajpgi.00077.2014
Camargo FD, Gokhale S, Johnnidis JB et al (2007) YAP1 increases organ size and expands undifferentiated progenitor cells. Curr Biol 17:2054–2060. doi:10.1016/j.cub.2007.10.039
Yu F-X, Meng Z, Plouffe SW, Guan K-L (2015) Hippo pathway regulation of gastrointestinal tissues. Annu Rev Physiol 77:201–227. doi:10.1146/annurev-physiol-021014-071733
Urtasun R, Latasa MU, Demartis MI et al (2011) Connective tissue growth factor autocriny in human hepatocellular carcinoma: oncogenic role and regulation by epidermal growth factor receptor/yes-associated protein-mediated activation. Hepatology 54:2149–2158. doi:10.1002/hep.24587
Zhao B, Ye X, Yu J et al (2008) TEAD mediates YAP-dependent gene induction and growth control. Genes Dev 22:1962–1971. doi:10.1101/gad.1664408
Avruch J, Zhou D, Fitamant J, Bardeesy N (2011) Mst1/2 signalling to Yap: gatekeeper for liver size and tumour development. Br J Cancer 104:24–32. doi:10.1038/sj.bjc.6606011
Song H, Mak KK, Topol L et al (2010) Mammalian Mst1 and Mst2 kinases play essential roles in organ size control and tumor suppression. Proc Natl Acad Sci USA 107:1431–1436. doi:10.1073/pnas.0911409107
Zhang N, Bai H, David KK et al (2010) The Merlin/NF2 tumor suppressor functions through the YAP oncoprotein to regulate tissue homeostasis in mammals. Dev Cell 19:27–38. doi:10.1016/j.devcel.2010.06.015
Benhamouche S, Curto M, Saotome I et al (2010) Nf2/Merlin controls progenitor homeostasis and tumorigenesis in the liver. Genes Dev 24:1718–1730. doi:10.1101/gad.1938710
Yimlamai D, Christodoulou C, Galli GG et al (2014) Hippo pathway activity influences liver cell fate. Cell 157:1324–1338. doi:10.1016/j.cell.2014.03.060
Perra A, Kowalik MA, Ghiso E et al (2014) YAP activation is an early event and a potential therapeutic target in liver cancer development. J Hepatol 61:1088–1096. doi:10.1016/j.jhep.2014.06.033
Fitamant J, Kottakis F, Benhamouche S et al (2015) YAP inhibition restores hepatocyte differentiation in advanced HCC. Cell Rep, Leading to Tumor Regression. doi:10.1016/j.celrep.2015.02.027
Friedman SL (2010) Evolving challenges in hepatic fibrosis. Nat Rev Gastroenterol Hepatol 7:425–436. doi:10.1038/nrgastro.2010.97
Lozano R, Naghavi M, Foreman K et al (2012) Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet 380:2095–2128. doi:10.1016/S0140-6736(12)61728-0
Hernandez-Gea V, Friedman SL (2011) Pathogenesis of liver fibrosis. Annu Rev Pathol 6:425–456. doi:10.1146/annurev-pathol-011110-130246
Racine-Samson L, Scoazec JY, D’Errico A et al (1996) The metabolic organization of the adult human liver: a comparative study of normal, fibrotic, and cirrhotic liver tissue. Hepatology 24:104–113. doi:10.1002/hep.510240118
D’Amico G, Garcia-Tsao G, Pagliaro L (2006) Natural history and prognostic indicators of survival in cirrhosis: a systematic review of 118 studies. J Hepatol 44:217–231. doi:10.1016/j.jhep.2005.10.013
Okabe H, Satoh S, Kato T et al (2001) Genome-wide analysis of gene expression in human hepatocellular carcinomas using cDNA microarray: identification of genes involved in viral carcinogenesis and tumor progression. Cancer Res 61:2129–2137
Jing H, Zhang G, Meng L et al (2014) Gradually elevated expression of Gankyrin during human hepatocarcinogenesis and its clinicopathological significance. Sci Rep 4:5503. doi:10.1038/srep05503
King LY, Canasto-Chibuque C, Johnson KB et al (2014) A genomic and clinical prognostic index for hepatitis C-related early-stage cirrhosis that predicts clinical deterioration. Gut. doi:10.1136/gutjnl-2014-307862
Mirpuri E, García-Trevijano ER, Castilla-Cortazar I et al (2002) Altered liver gene expression in CCl4-cirrhotic rats is partially normalized by insulin-like growth factor-I. Int J Biochem Cell Biol 34:242–252
Kalkuhl A, Kaestner K, Buchmann A, Schwarz M (1996) Expression of hepatocyte-enriched nuclear transcription factors in mouse liver tumours. Carcinogenesis 17:609–612
Hellerbrand C, Amann T, Schlegel J et al (2008) The novel gene MIA2 acts as a tumour suppressor in hepatocellular carcinoma. Gut 57:243–251. doi:10.1136/gut.2007.129544
Zeng X, Lin Y, Yin C et al (2011) Recombinant adenovirus carrying the hepatocyte nuclear factor-1alpha gene inhibits hepatocellular carcinoma xenograft growth in mice. Hepatology 54:2036–2047. doi:10.1002/hep.24647
Yue H-Y, Yin C, Hou J-L et al (2010) Hepatocyte nuclear factor 4alpha attenuates hepatic fibrosis in rats. Gut 59:236–246. doi:10.1136/gut.2008.174904
Ning B-F, Ding J, Yin C et al (2010) Hepatocyte nuclear factor 4 alpha suppresses the development of hepatocellular carcinoma. Cancer Res 70:7640–7651. doi:10.1158/0008-5472.CAN-10-0824
Hatzis P, Talianidis I (2001) Regulatory mechanisms controlling human hepatocyte nuclear factor 4alpha gene expression. Mol Cell Biol 21:7320–7330. doi:10.1128/MCB.21.21.7320-7330.2001
Hatzis P, Kyrmizi I, Talianidis I (2006) Mitogen-activated protein kinase-mediated disruption of enhancer-promoter communication inhibits hepatocyte nuclear factor 4alpha expression. Mol Cell Biol 26:7017–7029. doi:10.1128/MCB.00297-06
Maeda Y, Hwang-Verslues WW, Wei G et al (2006) Tumour suppressor p53 down-regulates the expression of the human hepatocyte nuclear factor 4alpha (HNF4alpha) gene. Biochem J 400:303–313. doi:10.1042/BJ20060614
Maeda Y, Seidel SD, Wei G et al (2002) Repression of hepatocyte nuclear factor 4alpha tumor suppressor p53: involvement of the ligand-binding domain and histone deacetylase activity. Mol Endocrinol 16:402–410. doi:10.1210/mend.16.2.0769
Charni M, Rivlin N, Molchadsky A et al (2014) p53 in liver pathologies-taking the good with the bad. J Mol Med 92:1229–1234. doi:10.1007/s00109-014-1223-5
Sun W, Ding J, Wu K et al (2011) Gankyrin-mediated dedifferentiation facilitates the tumorigenicity of rat hepatocytes and hepatoma cells. Hepatology 54:1259–1272. doi:10.1002/hep.24530
Walesky C, Edwards G, Borude P et al (2013) Hepatocyte nuclear factor 4 alpha deletion promotes diethylnitrosamine-induced hepatocellular carcinoma in rodents. Hepatology 57:2480–2490. doi:10.1002/hep.26251
Yin C, Lin Y, Zhang X et al (2008) Differentiation therapy of hepatocellular carcinoma in mice with recombinant adenovirus carrying hepatocyte nuclear factor-4alpha gene. Hepatology 48:1528–1539. doi:10.1002/hep.22510
Hwang-Verslues WW, Sladek FM (2008) Nuclear receptor hepatocyte nuclear factor 4alpha1 competes with oncoprotein c-Myc for control of the p21/WAF1 promoter. Mol Endocrinol 22:78–90. doi:10.1210/me.2007-0298
Hatziapostolou M, Polytarchou C, Aggelidou E et al (2011) An HNF4α-miRNA inflammatory feedback circuit regulates hepatocellular oncogenesis. Cell 147:1233–1247. doi:10.1016/j.cell.2011.10.043
Berasain C, Goñi S, Castillo J et al (2010) Impairment of pre-mRNA splicing in liver disease: mechanisms and consequences. World J Gastroenterol 16:3091–3102
Chettouh H, Fartoux L, Aoudjehane L et al (2013) Mitogenic insulin receptor-A is overexpressed in human hepatocellular carcinoma due to EGFR-mediated dysregulation of rna splicing factors. Cancer Res 73:3974–3986. doi:10.1158/0008-5472.CAN-12-3824
Berasain C, Elizalde M, Urtasun R, Castillo J (2014) Alterations in the expression and activity of pre-mRNA splicing factors in hepatocarcinogenesis. Hepatic Oncol 1(2):241–252
Alberstein M, Amit M, Vaknin K et al (2007) Regulation of transcription of the RNA splicing factor hSlu7 by Elk-1 and Sp1 affects alternative splicing. RNA 13:1988–1999. doi:10.1261/rna.492907
Castillo J, Goñi S, Latasa MU et al (2009) Amphiregulin induces the alternative splicing of p73 into its oncogenic isoform DeltaEx2p73 in human hepatocellular tumors. Gastroenterology 137(1805–15):e1–e4. doi:10.1053/j.gastro.2009.07.065
Elizalde M, Urtasun R, Azkona M et al (2014) Splicing regulator SLU7 is essential for maintaining liver homeostasis. J Clin Invest. doi:10.1172/JCI74382
Vander Heiden MG, Cantley LC, Thompson CB (2009) Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 324:1029–1033. doi:10.1126/science.1160809
Ward PS, Thompson CB (2012) Metabolic Reprogramming: a Cancer Hallmark Even Warburg Did Not Anticipate. Cancer Cell 21:297–308. doi:10.1016/j.ccr.2012.02.014
Nishikawa T, Bellance N, Damm A et al (2014) A switch in the source of ATP production and a loss in capacity to perform glycolysis are hallmarks of hepatocyte failure in advance liver disease. J Hepatol 60:1203–1211. doi:10.1016/j.jhep.2014.02.014
Sen S, Jumaa H, Webster NJG (2013) Splicing factor SRSF3 is crucial for hepatocyte differentiation and metabolic function. Nat Commun 4:1336. doi:10.1038/ncomms2342
Sen S, Langiewicz M, Jumaa H, Webster NJG (2015) Deletion of serine/arginine-rich splicing factor 3 in hepatocytes predisposes to hepatocellular carcinoma in mice. Hepatology 61:171–183. doi:10.1002/hep.27380
Gonzalez-Aseguinolaza G, Prieto J (2011) Gene therapy of liver diseases: a 2011 perspective. Clin Res Hepatol Gastroenterol 35:699–708. doi:10.1016/j.clinre.2011.05.016
Fan TT, Hu PF, Wang J et al (2013) Regression effect of hepatocyte nuclear factor 4α on liver cirrhosis in rats. J Dig Dis 14:318–327. doi:10.1111/1751-2980.12042
Lee YA, Wallace MC, Friedman SL (2015) Pathobiology of liver fibrosis: a translational success story. Gut. doi:10.1136/gutjnl-2014-306842
Garcia-Bañuelos J, Siller-Lopez F, Miranda A et al (2002) Cirrhotic rat livers with extensive fibrosis can be safely transduced with clinical-grade adenoviral vectors. Evidence cirrhosis reversion. Gene Ther 9:127–134. doi:10.1038/sj.gt.3301647
Sobrevals L, Enguita M, Rodriguez C et al (2012) AAV vectors transduce hepatocytes in vivo as efficiently in cirrhotic as in healthy rat livers. Gene Ther 19:411–417. doi:10.1038/gt.2011.119
Nishikawa T, Bell A, Brooks JM et al (2015) Resetting the transcription factor network reverses terminal chronic hepatic failure. J Clin Invest 125:1533–1544. doi:10.1172/JCI73137
Chandler RJ, LaFave MC, Varshney GK et al (2015) Vector design influences hepatic genotoxicity after adeno-associated virus gene therapy. J Clin Invest 125:870–880. doi:10.1172/JCI79213
Hareendran S, Balakrishnan B, Sen D et al (2013) Adeno-associated virus (AAV) vectors in gene therapy: immune challenges and strategies to circumvent them. Rev Med Virol 23:399–413. doi:10.1002/rmv.1762
Gougelet A, Sartor C, Bachelot L et al (2015) Antitumour activity of an inhibitor of miR-34a in liver cancer with β-catenin-mutations. Gut. doi:10.1136/gutjnl-2014-308969
Yin C, Wang P-Q, Xu W-P et al (2013) Hepatocyte nuclear factor-4α reverses malignancy of hepatocellular carcinoma through regulating miR-134 in the DLK1-DIO3 region. Hepatology 58:1964–1976. doi:10.1002/hep.26573
Otsuka M, Kishikawa T, Yoshikawa T et al (2014) The role of microRNAs in hepatocarcinogenesis: current knowledge and future prospects. J Gastroenterol 49:173–184. doi:10.1007/s00535-013-0909-8
Zhang Y, Wang Z, Gemeinhart RA (2013) Progress in microRNA delivery. J Control Release 172:962–974. doi:10.1016/j.jconrel.2013.09.015
Borel F, Kay MA, Mueller C (2014) Recombinant AAV as a platform for translating the therapeutic potential of RNA interference. Mol Ther 22:692–701. doi:10.1038/mt.2013.285
Lu SC, Mato JM (2012) s-adenosylmethionine in liver health, injury, and cancer. Physiol Rev 92:1515–1542. doi:10.1152/physrev.00047.2011
García-Trevijano ER, Latasa MU, Carretero MV et al (2000) s-adenosylmethionine regulates MAT1A and MAT2A gene expression in cultured rat hepatocytes: a new role for S-adenosylmethionine in the maintenance of the differentiated status of the liver. FASEB J 14:2511–2518
Latasa MU, Boukaba A, García-Trevijano ER et al (2001) Hepatocyte growth factor induces MAT2A expression and histone acetylation in rat hepatocytes: role in liver regeneration. FASEB J 15:1248–1250
Mato JM, Corrales FJ, Lu SC, Avila MA (2002) S-Adenosylmethionine: a control switch that regulates liver function. FASEB J 16:15–26. doi:10.1096/fj.01-0401rev
Anstee QM, Day CP (2012) S-adenosylmethionine (SAMe) therapy in liver disease: a review of current evidence and clinical utility. J Hepatol 57:1097–1109. doi:10.1016/j.jhep.2012.04.041
Liu-Chittenden Y, Huang B, Shim JS et al (2012) Genetic and pharmacological disruption of the TEAD-YAP complex suppresses the oncogenic activity of YAP. Genes Dev 26:1300–1305. doi:10.1101/gad.192856.112
Raju R, Chau D, Verfaillie CM, Hu W-S (2013) The road to regenerative liver therapies: the triumphs, trials and tribulations. Biotechnol Adv 31:1085–1093. doi:10.1016/j.biotechadv.2013.08.022
Sekiya S, Suzuki A (2011) Direct conversion of mouse fibroblasts to hepatocyte-like cells by defined factors. Nature 475:390–393. doi:10.1038/nature10263
Huang P, He Z, Ji S et al (2011) Induction of functional hepatocyte-like cells from mouse fibroblasts by defined factors. Nature 475:386–389. doi:10.1038/nature10116
Zhu S, Rezvani M, Harbell J et al (2014) Mouse liver repopulation with hepatocytes generated from human fibroblasts. Nature 508:93–97. doi:10.1038/nature13020
Anstee QM, Targher G, Day CP (2013) Progression of NAFLD to diabetes mellitus, cardiovascular disease or cirrhosis. Nat Rev Gastroenterol Hepatol 10:330–344. doi:10.1038/nrgastro.2013.41
Byrne CD, Targher G (2015) NAFLD: a multisystem disease. J Hepatol 62:S47–S64. doi:10.1016/j.jhep.2014.12.012
Acknowledgments
The work in the authors’ laboratory was funded by CIBEREHD, FIS PI10/02642, PI13/00359, PI10/00038 and PI13/00385, all from Instituto de Salud Carlos III (ISCIII) and co-financed by “Fondo Europeo de Desarrollo Regional” (FEDER) “Una manera de hacer Europa”.We thank all the current and past members of our laboratory.
Author information
Authors and Affiliations
Corresponding authors
Rights and permissions
About this article
Cite this article
Berasain, C., Avila, M.A. Regulation of hepatocyte identity and quiescence. Cell. Mol. Life Sci. 72, 3831–3851 (2015). https://doi.org/10.1007/s00018-015-1970-7
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00018-015-1970-7