Hepatocyte nuclear factor 4-alpha involvement in liver and intestinal inflammatory networks

World Journal of Gastroenterology

Volumn 20, Issue 1, 2014, Pages 22-30

  Babeu, Jean Philippe ^a   Boudreau, François ^a  

^a UNIVERSITÉ DE SHERBROOKE   (Canada)

Author keywords

Colitis associated cancer; Gastrointestinal tract; Hepatocyte nuclear factor 4 alpha; Inflammation; Inflammatory bowel diseases; Intestinal epithelium barrier

Indexed keywords

GLYCOGEN SYNTHASE KINASE 3BETA; HEPATOCYTE NUCLEAR FACTOR 4ALPHA; IMMUNOGLOBULIN ENHANCER BINDING PROTEIN; INTERLEUKIN 1BETA; INTERLEUKIN 6; MITOGEN ACTIVATED PROTEIN KINASE 7; SMAD2 PROTEIN; SMAD3 PROTEIN; STAT3 PROTEIN; TRANSFORMING GROWTH FACTOR BETA; TUMOR NECROSIS FACTOR ALPHA;

ACUTE PHASE RESPONSE; ARTICLE; CELL DIFFERENTIATION; CELL PROLIFERATION; DISEASE ASSOCIATION; ENTERITIS; GENE MUTATION; GENETIC ASSOCIATION; GENETIC SUSCEPTIBILITY; GENETIC TRANSCRIPTION; GENETIC VARIABILITY; HUMAN; INFLAMMATION; LIVER CELL; PROTEIN EXPRESSION; PROTEIN PHOSPHORYLATION;

COLITIS-ASSOCIATED CANCER; GASTROINTESTINAL TRACT; HEPATOCYTE NUCLEAR FACTOR 4-ALPHA; INFLAMMATION; INFLAMMATORY BOWEL DISEASES; INTESTINAL EPITHELIUM BARRIER;

ANIMALS; HEPATITIS; HEPATOCYTE NUCLEAR FACTOR 4; HEPATOCYTES; HUMANS; INFLAMMATION MEDIATORS; INFLAMMATORY BOWEL DISEASES; INTESTINAL MUCOSA; LIVER; PROTEIN ISOFORMS; SIGNAL TRANSDUCTION;

EID: 84891780760     PISSN: 10079327     EISSN: 22192840     Source Type: Journal    
DOI: 10.3748/wjg.v20.i1.22     Document Type: Article

References (58)

1. Kritis AA, Argyrokastritis A, Moschonas NK, Power S, Katrakili N, Zannis VI, Cereghini S, Talianidis I. Isolation and characterization of a third isoform of human hepatocyte nuclear factor 4. Gene 1996; 173: 275-280. [PMID: 8964514 DOI: 10.1016/0378-1119(96)00183-7]
2. Thomas H, Jaschkowitz K, Bulman M, Frayling TM, Mitchell SM, Roosen S, Lingott-Frieg A, Tack CJ, Ellard S, Ryffel GU, Hattersley AT. A distant upstream promoter of the HNF-4alpha gene connects the transcription factors involved in maturity-onset diabetes of the young. Hum Mol Genet 2001; 10: 2089-2097. [PMID: 11590126 DOI: 10.1093/ hmg/10.19.2089]
3. Drewes T, Senkel S, Holewa B, Ryffel GU. Human hepatocyte nuclear factor 4 isoforms are encoded by distinct and differentially expressed genes. Mol Cell Biol 1996; 16: 925-931. [PMID: 8622695]
4. Furuta H, Iwasaki N, Oda N, Hinokio Y, Horikawa Y, Yamagata K, Yano N, Sugahiro J, Ogata M, Ohgawara H, Omori Y, Iwamoto Y, Bell GI. Organization and partial sequence of the hepatocyte nuclear factor-4 alpha/MODY1 gene and identification of a missense mutation, R127W, in a Japanese family with MODY. Diabetes 1997; 46: 1652-1657. [PMID: 9313765 DOI: 10.2337/diacare.46.10.1652]
5. Hansen SK, Párrizas M, Jensen ML, Pruhova S, Ek J, Boj SF, Johansen A, Maestro MA, Rivera F, Eiberg H, Andel M, Lebl J, Pedersen O, Ferrer J, Hansen T. Genetic evidence that HNF-1alpha-dependent transcriptional control of HNF4alpha is essential for human pancreatic beta cell function. J Clin Invest 2002; 110: 827-833. [PMID: 12235114 DOI: 10.1172/JCI15085]
6. Nakhei H, Lingott A, Lemm I, Ryffel GU. An alternative splice variant of the tissue specific transcription factor HNF4alpha predominates in undifferentiated murine cell types. Nucleic Acids Res 1998; 26: 497-504. [PMID: 9421506 DOI: 10.1093/nar/26.2.497]
7. Briançon N, Weiss MC. In vivo role of the HNF4alpha AF-1 activation domain revealed by exon swapping. EMBO J 2006; 25: 1253-1262. [PMID: 16498401 DOI: 10.1038/ sj.emboj.7601021]
8. Tanaka T, Jiang S, Hotta H, Takano K, Iwanari H, Sumi K, Daigo K, Ohashi R, Sugai M, Ikegame C, Umezu H, Hirayama Y, Midorikawa Y, Hippo Y, Watanabe A, Uchiyama Y, Hasegawa G, Reid P, Aburatani H, Hamakubo T, Sakai J, Naito M, Kodama T. Dysregulated expression of P1 and P2 promoter-driven hepatocyte nuclear factor-4alpha in the pathogenesis of human cancer. J Pathol 2006; 208: 662-672. [PMID: 16400631 DOI: 10.1002/path.1928]
9. Torres-Padilla ME, Fougère-Deschatrette C, Weiss MC. Expression of HNF4alpha isoforms in mouse liver development is regulated by sequential promoter usage and constitutive 3' end splicing. Mech Dev 2001; 109: 183-193. [PMID: 11731232 DOI: 10.1016/S0925-4773(01)00521-4]
10. Boj SF, Parrizas M, Maestro MA, Ferrer J. A transcription factor regulatory circuit in differentiated pancreatic cells. Proc Natl Acad Sci USA 2001; 98: 14481-14486. [PMID: 11717395 DOI: 10.1073/pnas.241349398]
11. Briançon N, Bailly A, Clotman F, Jacquemin P, Lemaigre FP, Weiss MC. Expression of the alpha7 isoform of hepatocyte nuclear factor (HNF) 4 is activated by HNF6/OC-2 and HNF1 and repressed by HNF4alpha1 in the liver. J Biol Chem 2004; 279: 33398-33408. [PMID: 15159395 DOI: 10.1074/ jbc.M405312200]
12. Hatzis P, Talianidis I. Regulatory mechanisms controlling human hepatocyte nuclear factor 4alpha gene expression. Mol Cell Biol 2001; 21: 7320-7330. [PMID: 11585914 DOI: 10.1128/MCB.21.21.7320-7330.2001]
13. Ramamoorthy A, Li L, Gaedigk A, Bradford LD, Benson EA, Flockhart DA, Skaar TC. In silico and in vitro identification of microRNAs that regulate hepatic nuclear factor 4α expression. Drug Metab Dispos 2012; 40: 726-733. [PMID: 22232426 DOI: 10.1124/dmd.111.040329]
14. Takagi S, Nakajima M, Kida K, Yamaura Y, Fukami T, Yokoi T. MicroRNAs regulate human hepatocyte nuclear factor 4alpha, modulating the expression of metabolic enzymes and cell cycle. J Biol Chem 2010; 285: 4415-4422. [PMID: 20018894 DOI: 10.1074/jbc.M109.085431]
15. Wirsing A, Senkel S, Klein-Hitpass L, Ryffel GU. A systematic analysis of the 3'UTR of HNF4A mRNA reveals an interplay of regulatory elements including miRNA target sites. PLoS One 2011; 6: e27438. [PMID: 22140441 DOI: 10.1371/journal.pone.0027438]
16. Hatziapostolou M, Polytarchou C, Aggelidou E, Drakaki A, Poultsides GA, Jaeger SA, Ogata H, Karin M, Struhl K, Hadzopoulou-Cladaras M, Iliopoulos D. An HNF4α-miRNA inflammatory feedback circuit regulates hepatocellular oncogenesis. Cell 2011; 147: 1233-1247. [PMID: 22153071 DOI: 10.1016/j.cell.2011.10.043]
17. Chandra V, Holla P, Ghosh D, Chakrabarti D, Padigaru M, Jameel S. The hepatitis E virus ORF3 protein regulates the expression of liver-specific genes by modulating localization of hepatocyte nuclear factor 4. PLoS One 2011; 6: e22412. [PMID: 21799848 DOI: 10.1371/journal.pone.0022412]
18. Ktistaki E, Ktistakis NT, Papadogeorgaki E, Talianidis I. Recruitment of hepatocyte nuclear factor 4 into specific intranuclear compartments depends on tyrosine phosphorylation that affects its DNA-binding and transactivation potential. Proc Natl Acad Sci USA 1995; 92: 9876-9880. [PMID: 7568236 DOI: 10.1073/pnas.92.21.9876]
19. De Fabiani E, Mitro N, Anzulovich AC, Pinelli A, Galli G, Crestani M. The negative effects of bile acids and tumor necrosis factor-alpha on the transcription of cholesterol 7alpha-hydroxylase gene (CYP7A1) converge to hepatic nuclear factor-4: a novel mechanism of feedback regulation of bile acid synthesis mediated by nuclear receptors. J Biol Chem 2001; 276: 30708-30716. [PMID: 11402042 DOI: 10.1074/ jbc.M103270200]
20. Leclerc I, Lenzner C, Gourdon L, Vaulont S, Kahn A, Viollet B. Hepatocyte nuclear factor-4alpha involved in type 1 maturity-onset diabetes of the young is a novel target of AMPactivated protein kinase. Diabetes 2001; 50: 1515-1521. [PMID: 11423471 DOI: 10.2337/diabetes.50.7.1515]
21. Roy N, Guruprasad MR, Kondaiah P, Mann EA, Giannella RA, Visweswariah SS. Protein kinase C regulates transcription of the human guanylate cyclase C gene. Eur J Biochem 2001; 268: 2160-2171. [PMID: 11277940 DOI: 10.1046/ j.1432-1327.2001.02101.x]
22. Viollet B, Kahn A, Raymondjean M. Protein kinase A-dependent phosphorylation modulates DNA-binding activity of hepatocyte nuclear factor 4. Mol Cell Biol 1997; 17: 4208-4219. [PMID: 9234678]
23. Soutoglou E, Katrakili N, Talianidis I. Acetylation regulates transcription factor activity at multiple levels. Mol Cell 2000; 5: 745-751. [PMID: 10882110]
24. Lucas SD, López-Alcorocho JM, Bartolomé J, Carreño V. Nitric oxide and TGF-beta1 inhibit HNF-4alpha function in HEPG2 cells. Biochem Biophys Res Commun 2004; 321: 688-694. [PMID: 15358161 DOI: 10.1016/j.bbrc.2004.07.025]
25. Chellappa K, Jankova L, Schnabl JM, Pan S, Brelivet Y, Fung CL, Chan C, Dent OF, Clarke SJ, Robertson GR, Sladek FM. Src tyrosine kinase phosphorylation of nuclear receptor HNF4α correlates with isoform-specific loss of HNF4α in human colon cancer. Proc Natl Acad Sci USA 2012; 109: 2302-2307. [PMID: 22308320 DOI: 10.1073/pnas.1106799109]
26. Hayhurst GP, Lee YH, Lambert G, Ward JM, Gonzalez FJ. Hepatocyte nuclear factor 4alpha (nuclear receptor 2A1) is essential for maintenance of hepatic gene expression and lipid homeostasis. Mol Cell Biol 2001; 21: 1393-1403. [PMID: 11158324 DOI: 10.1128/MCB.21.4.1393-1403.2001]
27. Parviz F, Matullo C, Garrison WD, Savatski L, Adamson JW, Ning G, Kaestner KH, Rossi JM, Zaret KS, Duncan SA. Hepatocyte nuclear factor 4alpha controls the development of a hepatic epithelium and liver morphogenesis. Nat Genet 2003; 34: 292-296. [PMID: 12808453 DOI: 10.1038/ng1175]
28. Bolotin E, Liao H, Ta TC, Yang C, Hwang-Verslues W, Evans JR, Jiang T, Sladek FM. Integrated approach for the identification of human hepatocyte nuclear factor 4alpha target genes using protein binding microarrays. Hepatology 2010; 51: 642-653. [PMID: 20054869 DOI: 10.1002/hep.23357]
29. Battle MA, Konopka G, Parviz F, Gaggl AL, Yang C, Sladek FM, Duncan SA. Hepatocyte nuclear factor 4alpha orchestrates expression of cell adhesion proteins during the epithelial transformation of the developing liver. Proc Natl Acad Sci USA 2006; 103: 8419-8424. [PMID: 16714383 DOI: 10.1073/pnas.0600246103]
30. Wang Z, Bishop EP, Burke PA. Expression profile analysis of the inflammatory response regulated by hepatocyte nuclear factor 4α. BMC Genomics 2011; 12: 128. [PMID: 21352552 DOI: 10.1186/1471-2164-12-128]
31. Odom DT, Zizlsperger N, Gordon DB, Bell GW, Rinaldi NJ, Murray HL, Volkert TL, Schreiber J, Rolfe PA, Gifford DK, Fraenkel E, Bell GI, Young RA. Control of pancreas and liver gene expression by HNF transcription factors. Science 2004; 303: 1378-1381. [PMID: 14988562 DOI: 10.1126/science.1089769]
32. Guo H, Gao C, Mi Z, Wai PY, Kuo PC. Phosphorylation of Ser158 regulates inflammatory redox-dependent hepatocyte nuclear factor-4alpha transcriptional activity. Biochem J 2006; 394: 379-387. [PMID: 16351573 DOI: 10.1042/BJ20051730]
33. Simó R, Barbosa-Desongles A, Hernandez C, Selva DM. IL1β down-regulation of sex hormone-binding globulin production by decreasing HNF-4α via MEK-1/2 and JNK MAPK pathways. Mol Endocrinol 2012; 26: 1917-1927. [PMID: 22902540 DOI: 10.1210/me.2012-1152]
34. Li T, Chiang JY. A novel role of transforming growth factor beta1 in transcriptional repression of human cholesterol 7alpha-hydroxylase gene. Gastroenterology 2007; 133: 1660-1669. [PMID: 17920062 DOI: 10.1053/j.gastro.2007.08.042]
35. Cozzolino AM, Alonzi T, Santangelo L, Mancone C, Conti B, Steindler C, Musone M, Cicchini C, Tripodi M, Marchetti A. TGFβ overrides HNF4α tumor suppressing activity through GSK3β inactivation: implication for hepatocellular carcinoma gene therapy. J Hepatol 2013; 58: 65-72. [PMID: 22960426 DOI: 10.1016/j.jhep.2012.08.023]
36. Mizutani A, Koinuma D, Tsutsumi S, Kamimura N, Morikawa M, Suzuki HI, Imamura T, Miyazono K, Aburatani H. Cell type-specific target selection by combinatorial binding of Smad2/3 proteins and hepatocyte nuclear factor 4alpha in HepG2 cells. J Biol Chem 2011; 286: 29848-29860. [PMID: 21646355 DOI: 10.1074/jbc.M110.217745]
37. Nikolaidou-Neokosmidou V, Zannis VI, Kardassis D. Inhibition of hepatocyte nuclear factor 4 transcriptional activity by the nuclear factor kappaB pathway. Biochem J 2006; 398: 439-450. [PMID: 16771709 DOI: 10.1042/BJ20060169]
38. Wang Z, Burke PA. Modulation of hepatocyte nuclear factor-4alpha function by the peroxisome-proliferator-activated receptor-gamma co-activator-1alpha in the acute-phase response. Biochem J 2008; 415: 289-296. [PMID: 18510493 DOI: 10.1042/BJ20080355]
39. Bauzá G, Miller G, Kaseje N, Wang Z, Sherburne A, Agarwal S, Burke PA. Injury-induced changes in liver specific transcription factors HNF-1α and HNF-4α. J Surg Res 2012; 175: 298-304. [PMID: 21737100 DOI: 10.1016/j.jss.2011.04.062]
40. Garrison WD, Battle MA, Yang C, Kaestner KH, Sladek FM, Duncan SA. Hepatocyte nuclear factor 4alpha is essential for embryonic development of the mouse colon. Gastroenterology 2006; 130: 1207-1220. [PMID: 16618389 DOI: 10.1053/ j.gastro.2006.01.003]
41. Babeu JP, Darsigny M, Lussier CR, Boudreau F. Hepatocyte nuclear factor 4alpha contributes to an intestinal epithelial phenotype in vitro and plays a partial role in mouse intestinal epithelium differentiation. Am J Physiol Gastrointest Liver Physiol 2009; 297: G124-G134. [PMID: 19389805 DOI: 10.1152/ajpgi.90690.2008]
42. Cattin AL, Le Beyec J, Barreau F, Saint-Just S, Houllier A, Gonzalez FJ, Robine S, Pinçon-Raymond M, Cardot P, Lacasa M, Ribeiro A. Hepatocyte nuclear factor 4alpha, a key factor for homeostasis, cell architecture, and barrier function of the adult intestinal epithelium. Mol Cell Biol 2009; 29: 6294-6308. [PMID: 19805521 DOI: 10.1128/MCB.00939-09]
43. Lussier CR, Babeu JP, Auclair BA, Perreault N, Boudreau F. Hepatocyte nuclear factor-4alpha promotes differentiation of intestinal epithelial cells in a coculture system. Am J Physiol Gastrointest Liver Physiol 2008; 294: G418-G428. [PMID: 18032476 DOI: 10.1152/ajpgi.00418.2007]
44. Archer A, Sauvaget D, Chauffeton V, Bouchet PE, Chambaz J, Pinçon-Raymond M, Cardot P, Ribeiro A, Lacasa M. Intestinal apolipoprotein A-IV gene transcription is controlled by two hormone-responsive elements: a role for hepatic nuclear factor-4 isoforms. Mol Endocrinol 2005; 19: 2320-2334. [PMID: 15928313]
45. Stegmann A, Hansen M, Wang Y, Larsen JB, Lund LR, Ritié L, Nicholson JK, Quistorff B, Simon-Assmann P, Troelsen JT, Olsen J. Metabolome, transcriptome, and bioinformatic cis-element analyses point to HNF-4 as a central regulator of gene expression during enterocyte differentiation. Physiol Genomics 2006; 27: 141-155. [PMID: 16868071 DOI: 10.1152/ physiolgenomics.00314.2005]
46. Chiba H, Gotoh T, Kojima T, Satohisa S, Kikuchi K, Osanai M, Sawada N. Hepatocyte nuclear factor (HNF)-4alpha triggers formation of functional tight junctions and establishment of polarized epithelial morphology in F9 embryonal carcinoma cells. Exp Cell Res 2003; 286: 288-297. [PMID: 12749857 DOI: 10.1016/S0014-4827(03)00116-2]
47. Darsigny M, Babeu JP, Dupuis AA, Furth EE, Seidman EG, Lévy E, Verdu EF, Gendron FP, Boudreau F. Loss of hepatocyte-nuclear-factor-4alpha affects colonic ion transport and causes chronic inflammation resembling inflammatory bowel disease in mice. PLoS One 2009; 4: e7609. [PMID: 19898610 DOI: 10.1371/journal.pone.0007609]
48. Ahn SH, Shah YM, Inoue J, Morimura K, Kim I, Yim S, Lambert G, Kurotani R, Nagashima K, Gonzalez FJ, Inoue Y. Hepatocyte nuclear factor 4alpha in the intestinal epithelial cells protects against inflammatory bowel disease. Inflamm Bowel Dis 2008; 14: 908-920. [PMID: 18338782 DOI: 10.1002/ ibd.20413]
49. Barrett JC, Lee JC, Lees CW, Prescott NJ, Anderson CA, Phillips A, Wesley E, Parnell K, Zhang H, Drummond H, Nimmo ER, Massey D, Blaszczyk K, Elliott T, Cotterill L, Dallal H, Lobo AJ, Mowat C, Sanderson JD, Jewell DP, Newman WG, Edwards C, Ahmad T, Mansfield JC, Satsangi J, Parkes M, Mathew CG, Donnelly P, Peltonen L, Blackwell JM, Bramon E, Brown MA, Casas JP, Corvin A, Craddock N, Deloukas P, Duncanson A, Jankowski J, Markus HS, Mathew CG, McCarthy MI, Palmer CN, Plomin R, Rautanen A, Sawcer SJ, Samani N, Trembath RC, Viswanathan AC, Wood N, Spencer CC, Barrett JC, Bellenguez C, Davison D, Freeman C, Strange A, Donnelly P, Langford C, Hunt SE, Edkins S, Gwilliam R, Blackburn H, Bumpstead SJ, Dronov S, Gillman M, Gray E, Hammond N, Jayakumar A, McCann OT, Liddle J, Perez ML, Potter SC, Ravindrarajah R, Ricketts M, Waller M, Weston P, Widaa S, Whittaker P, Deloukas P, Peltonen L, Mathew CG, Blackwell JM, Brown MA, Corvin A, McCarthy MI, Spencer CC, Attwood AP, Stephens J, Sambrook J, Ouwehand WH, McArdle WL, Ring SM, Strachan DP. Genome-wide association study of ulcerative colitis identifies three new susceptibility loci, including the HNF4A region. Nat Genet 2009; 41: 1330-1334. [PMID: 19915572 DOI: 10.1038/ng.483]
50. van Sommeren S, Visschedijk MC, Festen EA, de Jong DJ, Ponsioen CY, Wijmenga C, Weersma RK. HNF4α and CDH1 are associated with ulcerative colitis in a Dutch cohort. Inflamm Bowel Dis 2011; 17: 1714-1718. [PMID: 21744425 DOI: 10.1002/ibd.21541]
51. Marcil V, Sinnett D, Seidman E, Boudreau F, Gendron FP, Beaulieu JF, Menard D, Lambert M, Bitton A, Sanchez R, Amre D, Levy E. Association between genetic variants in the HNF4A gene and childhood-onset Crohn's disease. Genes Immun 2012; 13: 556-565. [PMID: 22914433 DOI: 10.1038/ gene.2012.37]
52. Koukos G, Polytarchou C, Kaplan JL, Morley-Fletcher A, Gras-Miralles B, Kokkotou E, Baril-Dore M, Pothoulakis C, Winter HS, Iliopoulos D. MicroRNA-124 regulates STAT3 expression and is down-regulated in colon tissues of pediatric patients with ulcerative colitis. Gastroenterology 2013; 145: 842-852. [PMID: 23856509 DOI: 10.1053/ j.gastro.2013.07.001]
53. Bollrath J, Phesse TJ, von Burstin VA, Putoczki T, Bennecke M, Bateman T, Nebelsiek T, Lundgren-May T, Canli O, Schwitalla S, Matthews V, Schmid RM, Kirchner T, Arkan MC, Ernst M, Greten FR. gp130-mediated Stat3 activation in enterocytes regulates cell survival and cell-cycle progression during colitis-associated tumorigenesis. Cancer Cell 2009; 15: 91-102. [PMID: 19185844 DOI: 10.1016/j.ccr.2009.01.002]
54. Grivennikov S, Karin E, Terzic J, Mucida D, Yu GY, Vallabhapurapu S, Scheller J, Rose-John S, Cheroutre H, Eckmann L, Karin M. IL-6 and Stat3 are required for survival of intestinal epithelial cells and development of colitis-associated cancer. Cancer Cell 2009; 15: 103-113. [PMID: 19185845 DOI: 10.1016/j.ccr.2009.01.001]
55. Lazarevich NL, Shavochkina DA, Fleishman DI, Kustova IF, Morozova OV, Chuchuev ES, Patyutko YI. Deregulation of hepatocyte nuclear factor 4 (HNF4)as a marker of epithelial tumors progression. Exp Oncol 2010; 32: 167-171. [PMID: 21403612]
56. Bonzo JA, Ferry CH, Matsubara T, Kim JH, Gonzalez FJ. Suppression of hepatocyte proliferation by hepatocyte nuclear factor 4α in adult mice. J Biol Chem 2012; 287: 7345-7356. [PMID: 22241473 DOI: 10.1074/jbc.M111.334599]
57. Rieck S, Zhang J, Li Z, Liu C, Naji A, Takane KK, FiaschiTaesch NM, Stewart AF, Kushner JA, Kaestner KH. Over expression of hepatocyte nuclear factor-4α initiates cell cycle entry, but is not sufficient to promote β-cell expansion in human islets. Mol Endocrinol 2012; 26: 1590-1602. [PMID: 22798294 DOI: 10.1210/me.2012-1019]
58. Walesky C, Gunewardena S, Terwilliger EF, Edwards G, Borude P, Apte U. Hepatocyte-specific deletion of hepatocyte nuclear factor-4α in adult mice results in increased hepatocyte proliferation. Am J Physiol Gastrointest Liver Physiol 2013; 304: G26-G37. [PMID: 23104559 DOI: 10.1152/ ajpgi.00064.2012]