Molecular mechanisms of liver regeneration and protection for treatment of liver dysfunction and diseases

Journal of Hepato-Biliary-Pancreatic Sciences

Volumn 18, Issue 1, 2011, Pages 13-22

  Fujiyoshi, Masato ^a   Ozaki, Michitaka ^a  

^a HOKKAIDO UNIVERSITY   (Japan)

Author keywords

Apoptosis; IL 6 STAT3; Liver protection; Liver regeneration; PI3 K PDK1 Akt

Indexed keywords

CASPASE 8; CASPASE 9; DNA; INTERLEUKIN 6; MAMMALIAN TARGET OF RAPAMYCIN; MATRIX METALLOPROTEINASE; PHOSPHATIDYLINOSITOL 3 KINASE; PHOSPHOINOSITIDE DEPENDENT PROTEIN KINASE 1; SCATTER FACTOR; STAT3 PROTEIN; TUMOR NECROSIS FACTOR ALPHA; PROTEIN KINASE B; PROTEIN SERINE THREONINE KINASE; S6 KINASE; SIGNAL PEPTIDE; STAT3 PROTEIN, MOUSE;

CELL CYCLE PROGRESSION; CELL FUNCTION; CELL INTERACTION; CELL PROLIFERATION; CYTOKINE RELEASE; DEVELOPMENTAL GENE; DNA SYNTHESIS; GENE EXPRESSION REGULATION; GENE TARGETING; HUMAN; INTERLEUKIN 6 GENE; INTRACELLULAR SIGNALING; LIVER DYSFUNCTION; LIVER PROTECTION; LIVER REGENERATION; MOLECULAR DYNAMICS; NONHUMAN; PROTEIN BINDING; PROTEIN EXPRESSION; PROTEIN FUNCTION; REVIEW; STAT3 GENE; TUMOR NECROSIS FACTOR ALPHA GENE; ANIMAL; APOPTOSIS; BIOSYNTHESIS; CYTOLOGY; KUPFFER CELL; LIVER; LIVER CELL; LIVER DISEASE; MOUSE; PATHOLOGY; PHYSIOLOGY; RAT; SIGNAL TRANSDUCTION;

ANIMALS; APOPTOSIS; CELL PROLIFERATION; HEPATOCYTES; INTERCELLULAR SIGNALING PEPTIDES AND PROTEINS; INTERLEUKIN-6; KUPFFER CELLS; LIVER; LIVER DISEASES; LIVER REGENERATION; MICE; PHOSPHATIDYLINOSITOL 3-KINASES; PROTEIN-SERINE-THREONINE KINASES; PROTO-ONCOGENE PROTEINS C-AKT; RATS; RIBOSOMAL PROTEIN S6 KINASES, 70-KDA; SIGNAL TRANSDUCTION; STAT3 TRANSCRIPTION FACTOR;

EID: 79957791258     PISSN: 18686974     EISSN: 18686982     Source Type: Journal    
DOI: 10.1007/s00534-010-0304-2     Document Type: Review

References (100)

1. Viebahn CS, Yeoh GC. What fires Prometheus? The link between inflammation and regeneration following chronic liver injury. Int J Biochem Cell Biol. 2008;40(5):855-73.
2. Pahlavan PS, Feldmann RE Jr, Zavos C, Kountouras J. Prometheus' challenge: molecular, cellular and systemic aspects of liver regeneration. J Surg Res. 2006;134(2):238-51.
3. Taub R. Liver regeneration: from myth to mechanism. Nat Rev Mol Cell Biol. 2004;5(10):836-47.
4. Moro L, Marra E, Capuano F, Greco M. Thyroid hormone treatment of hypothyroid rats restores the regenerative capacity and the mitochondrial membrane permeability properties of the liver after partial hepatectomy. Endocrinology. 2004;145(11):5121-8.
5. Malik R, Habib M, Tootle R, Hodgson H. Exogenous thyroid hormone induces liver enlargement, whilst maintaining regenerative potential - a study relevant to donor preconditioning. Am J Transplant. 2005;5(8):1801-7.
6. Kopplow K, Wayss K, Enzmann H, Mayer D. Dehydroepiandrosterone causes hyperplasia and impairs regeneration in rat liver. Int J Oncol. 2005;27(6):1551-8.
7. Sabugal R, Robert MQ, Julve J, Auwerx J, Llobera M, Peinado-Onsurbe J. Hepatic regeneration induces changes in lipoprotein lipase activity in several tissues and its re-expression in the liver. Biochem J. 1996;318(Pt 2):597-602.
8. Tang TX, Hashimoto T, Chao LY, Itoh K, Manabe T. Effects of partial pancreatectomy on liver regeneration in rats. J Surg Res. 1997;72(1):8-14.
9. Marti U, Burwen SJ, Jones AL. Biological effects of epidermal growth factor, with emphasis on the gastrointestinal tract and liver: an update. Hepatology. 1989;9(1):126-38.
10. Kiba T. The role of the autonomic nervous system in liver regeneration and apoptosis - recent developments. Digestion. 2002;66(2):79-88.
11. Huda KA, Guo L, Haga S, Murata H, Ogino T, Fukai M, et al. Ex vivo adenoviral gene transfer of constitutively activated STAT3 reduces post-transplant liver injury and promotes regeneration in a 20% rat partial liver transplant model. Transpl Int. 2006;19(5):415-23.
12. Webber EM, Bruix J, Pierce RH, Fausto N. Tumor necrosis factor primes hepatocytes for DNA replication in the rat. Hepatology. 1998;28(5):1226-34.
13. Cornell RP, Liljequist BL, Bartizal KF. Depressed liver regeneration after partial hepatectomy of germ-free, athymic and lipopolysaccharide-resistant mice. Hepatology. 1990;11(6):916-22.
14. Strey CW, Markiewski M, Mastellos D, Tudoran R, Spruce LA, Greenbaum LE, et al. The proinflammatory mediators C3a and C5a are essential for liver regeneration. J Exp Med. 2003;198(6):913-23.
15. Selzner N, Selzner M, Odermatt B, Tian Y, Van Rooijen N, Clavien PA. ICAM-1 triggers liver regeneration through leukocyte recruitment and Kupffer cell-dependent release of TNF-alpha/IL-6 in mice. Gastroenterology. 2003;124(3):692-700.
16. Libermann TA, Baltimore D. Activation of interleukin-6 gene expression through the NF-kappa B transcription factor. Mol Cell Biol. 1990;10(5):2327-34.
17. Zimmers TA, McKillop IH, Pierce RH, Yoo JY, Koniaris LG. Massive liver growth in mice induced by systemic interleukin 6 administration. Hepatology. 2003;38(2):326-34.
18. Cressman DE, Greenbaum LE, DeAngelis RA, Ciliberto G, Furth EE, Poli V, et al. Liver failure and defective hepatocyte regeneration in interleukin-6-deficient mice. Science. 1996;274(5291):1379-83.
19. Huh CG, Factor VM, Sanchez A, Uchida K, Conner EA, Thorgeirsson SS. Hepatocyte growth factor/c-met signaling pathway is required for efficient liver regeneration and repair. Proc Natl Acad Sci USA. 2004;101(13):4477-82.
20. Kim TH, Mars WM, Stolz DB, Petersen BE, Michalopoulos GK. Extracellular matrix remodeling at the early stages of liver regeneration in the rat. Hepatology. 1997;26(4):896-904.
21. Mohammed FF, Pennington CJ, Kassiri Z, Rubin JS, Soloway PD, Ruther U, et al. Metalloproteinase inhibitor TIMP-1 affects hepatocyte cell cycle via HGF activation in murine liver regeneration. Hepatology. 2005;41(4):857-67.
22. Borowiak M, Garratt AN, Wustefeld T, Strehle M, Trautwein C, Birchmeier C. Met provides essential signals for liver regeneration. Proc Natl Acad Sci USA. 2004;101(29):10608-13.
23. Okano J, Shiota G, Matsumoto K, Yasui S, Kurimasa A, Hisatome I, et al. Hepatocyte growth factor exerts a proliferative effect on oval cells through the PI3K/AKT signaling pathway. Biochem Biophys Res Commun. 2003;309(2):298-304.
24. Scheving LA, Stevenson MC, Taylormoore JM, Traxler P, Russell WE. Integral role of the EGF receptor in HGF-mediated hepatocyte proliferation. Biochem Biophys Res Commun. 2002;290(1):197-203.
25. Tomiya T, Ogata I, Yamaoka M, Yanase M, Inoue Y, Fujiwara K. The mitogenic activity of hepatocyte growth factor on rat hepatocytes is dependent upon endogenous transforming growth factor-alpha. Am J Pathol. 2000;157(5):1693-701.
26. Fausto N, Campbell JS, Riehle KJ. Liver regeneration. Hepatology. 2006;43(2 Suppl 1):S45-53.
27. Cressman DE, Diamond RH, Taub R. Rapid activation of the Stat3 transcription complex in liver regeneration. Hepatology. 1995;21(5):1443-9.
28. Akira S. Roles of STAT3 defined by tissue-specific gene targeting. Oncogene. 2000;19(21):2607-11.
29. Waelput W, Verhee A, Broekaert D, Eyckerman S, Vandekerckhove J, Beattie JH, et al. Identification and expression analysis of leptin-regulated immediate early response and late target genes. Biochem J. 2000;348(Pt 1):55-61.
30. Levy DE, Lee CK. What does Stat3 do? J Clin Invest. 2002;109(9):1143-8.
31. Schindler CW. Series introduction. JAK-STAT signaling in human disease. J Clin Invest. 2002;109(9):1133-7.
32. Darnell JE Jr, Kerr IM, Stark GR. Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins. Science. 1994;264(5164):1415-21.
33. Darnell JE Jr. STATs and gene regulation. Science. 1997;277(5332):1630-5.
34. Bromberg J, Darnell JE Jr. The role of STATs in transcriptional control and their impact on cellular function. Oncogene. 2000;19(21):2468-73.
35. Li W, Liang X, Kellendonk C, Poli V, Taub R. STAT3 contributes to the mitogenic response of hepatocytes during liver regeneration. J Biol Chem. 2002;277(32):28411-7.
36. Takeda K, Noguchi K, Shi W, Tanaka T, Matsumoto M, Yoshida N, et al. Targeted disruption of the mouse Stat3 gene leads to early embryonic lethality. Proc Natl Acad Sci USA. 1997;94(8):3801-4.
37. Bromberg JF, Wrzeszczynska MH, Devgan G, Zhao Y, Pestell RG, Albanese C, et al. Stat3 as an oncogene. Cell. 1999;98(3):295-303.
38. Terui K, Ozaki M. The role of STAT3 in liver regeneration. Drugs Today (Barc). 2005;41(7):461-9.
39. Loyer P, Cariou S, Glaise D, Bilodeau M, Baffet G, Guguen-Guillouzo C. Growth factor dependence of progression through G1 and S phases of adult rat hepatocytes in vitro. Evidence of a mitogen restriction point in mid-late G1. J Biol Chem. 1996;271(19):11484-92.
40. Lavia P, Jansen-Durr P. E2F target genes and cell-cycle checkpoint control. Bioessays. 1999;21(3):221-30.
41. Takahashi-Yanaga F, Sasaguri T. GSK-3beta regulates cyclin D1 expression: a new target for chemotherapy. Cell Signal. 2008;20(4):581-9.
42. Georgiev P, Dahm F, Graf R, Clavien PA. Blocking the path to death: anti-apoptotic molecules in ischemia/reperfusion injury of the liver. Curr Pharm Des. 2006;12(23):2911-21.
43. Clarke P, Tyler KL. Apoptosis in animal models of virus-induced disease. Nat Rev Microbiol. 2009;7(2):144-55.
44. Liu YG, Liu SX, Liang XH, Zhang Q, Gao LF, Han LH, et al. Blockade of TRAIL pathway ameliorates HBV-induced hepatocyte apoptosis in an acute hepatitis model. Biochem Biophys Res Commun. 2007;352(2):329-34.
45. Sheridan JP, Marsters SA, Pitti RM, Gurney A, Skubatch M, Baldwin D, et al. Control of TRAIL-induced apoptosis by a family of signaling and decoy receptors. Science. 1997;277(5327):818-21.
46. Boya P, Pauleau AL, Poncet D, Gonzalez-Polo RA, Zamzami N, Kroemer G. Viral proteins targeting mitochondria: controlling cell death. Biochim Biophys Acta. 2004;1659(2-3):178-89.
47. Okuda M, Li K, Beard MR, Showalter LA, Scholle F, Lemon SM, et al. Mitochondrial injury, oxidative stress, and antioxidant gene expression are induced by hepatitis C virus core protein. Gastroenterology. 2002;122(2):366-75.
48. Leifeld L, Nattermann J, Fielenbach M, Schmitz V, Sauerbruch T, Spengler U. Intrahepatic activation of caspases in human fulminant hepatic failure. Liver Int. 2006;26(7):872-9.
49. Kovalovich K, Li W, DeAngelis R, Greenbaum LE, Ciliberto G, Taub R. Interleukin-6 protects against Fas-mediated death by establishing a critical level of anti-apoptotic hepatic proteins FLIP, Bcl-2, and Bcl-xL. J Biol Chem. 2001;276(28):26605-13.
50. Pennarun B, Meijer A, de Vries EG, Kleibeuker JH, Kruyt F, de Jong S. Playing the DISC: turning on TRAIL death receptor-mediated apoptosis in cancer. Biochim Biophys Acta. 2010;1805(2):123-40.
51. Kruidering M, Evan GI. Caspase-8 in apoptosis: the beginning of "the end"? IUBMB Life. 2000;50(2):85-90.
52. Chipuk JE, Green DR. How do BCL-2 proteins induce mitochondrial outer membrane permeabilization? Trends Cell Biol. 2008;18(4):157-64.
53. Haga S, Terui K, Zhang HQ, Enosawa S, Ogawa W, Inoue H, et al. Stat3 protects against Fas-induced liver injury by redox-dependent and -independent mechanisms. J Clin Invest. 2003;112(7):989-98.
54. Terui K, Enosawa S, Haga S, Zhang HQ, Kuroda H, Kouchi K, et al. Stat3 confers resistance against hypoxia/reoxygenation-induced oxidative injury in hepatocytes through upregulation of Mn-SOD. J Hepatol. 2004;41(6):957-65.
55. Vetelainen R, van Vliet A, Gouma DJ, van Gulik TM. Steatosis as a risk factor in liver surgery. Ann Surg. 2007;245(1):20-30.
56. Kooby DA, Fong Y, Suriawinata A, Gonen M, Allen PJ, Klimstra DS, et al. Impact of steatosis on perioperative outcome following hepatic resection. J Gastrointest Surg. 2003;7(8):1034-44.
57. Sauer P, Schemmer P, Uhl W, Encke J. Living-donor liver transplantation: evaluation of donor and recipient. Nephrol Dial Transplant. 2004;19(Suppl 1):4. (iv11-5).
58. Imber CJ, St Peter SD, Handa A, Friend PJ. Hepatic steatosis and its relationship to transplantation. Liver Transpl. 2002;8(5):415-23.
59. Crowley H, Lewis WD, Gordon F, Jenkins R, Khettry U. Steatosis in donor and transplant liver biopsies. Hum Pathol. 2000;31(10):1209-13.
60. Akabayashi A, Slingsby BT, Fujita M. The first donor death after living-related liver transplantation in Japan. Transplantation. 2004;77(4):634.
61. Yamamoto K, Takada Y, Fujimoto Y, Haga H, Oike F, Kobayashi N, et al. Nonalcoholic steatohepatitis in donors for living donor liver transplantation. Transplantation. 2007;83(3):257-62.
62. Murata H, Yagi T, Iwagaki H, Ogino T, Sadamori H, Matsukawa H, et al. Mechanism of impaired regeneration of fatty liver in mouse partial hepatectomy model. J Gastroenterol Hepatol. 2007;22(12):2173-80.
63. Torbenson M, Yang SQ, Liu HZ, Huang J, Gage W, Diehl AM. STAT-3 overexpression and p21 up-regulation accompany impaired regeneration of fatty livers. Am J Pathol. 2002;161(1):155-61.
64. Wu H, Wade M, Krall L, Grisham J, Xiong Y, Van Dyke T. Targeted in vivo expression of the cyclin-dependent kinase inhibitor p21 halts hepatocyte cell-cycle progression, postnatal liver development and regeneration. Genes Dev. 1996;10(3):245-60.
65. Chin YE, Kitagawa M, Su WC, You ZH, Iwamoto Y, Fu XY. Cell growth arrest and induction of cyclin-dependent kinase inhibitor p21 WAF1/CIP1 mediated by STAT1. Science. 1996;272(5262):719-22.
66. Tanaka Y, Gavrielides MV, Mitsuuchi Y, Fujii T, Kazanietz MG. Protein kinase C promotes apoptosis in LNCaP prostate cancer cells through activation of p38 MAPK and inhibition of the Akt survival pathway. J Biol Chem. 2003;278(36):33753-62.
67. Conery AR, Cao Y, Thompson EA, Townsend CM Jr, Ko TC, Luo K. Akt interacts directly with Smad3 to regulate the sensitivity to TGF-beta induced apoptosis. Nat Cell Biol. 2004;6(4):366-72.
68. Gardai SJ, Hildeman DA, Frankel SK, Whitlock BB, Frasch SC, Borregaard N, et al. Phosphorylation of Bax Ser184 by Akt regulates its activity and apoptosis in neutrophils. J Biol Chem. 2004;279(20):21085-95.
69. Lu Y, Parkyn L, Otterbein LE, Kureishi Y, Walsh K, Ray A, et al. Activated Akt protects the lung from oxidant-induced injury and delays death of mice. J Exp Med. 2001;193(4):545-9.
70. Ozaki M, Haga S, Zhang HQ, Irani K, Suzuki S. Inhibition of hypoxia/reoxygenation-induced oxidative stress in HGF-stimulated antiapoptotic signaling: role of PI3-K and Akt kinase upon rac1. Cell Death Differ. 2003;10(5):508-15.
71. Pende M, Kozma SC, Jaquet M, Oorschot V, Burcelin R, Le Marchand-Brustel Y, et al. Hypoinsulinaemia, glucose intolerance and diminished beta-cell size in S6K1-deficient mice. Nature. 2000;408(6815):994-7.
72. Edinger AL, Thompson CB. Akt maintains cell size and survival by increasing mTOR-dependent nutrient uptake. Mol Biol Cell. 2002;13(7):2276-88.
73. G-Amlak M, Uddin S, Mahmud D, Damacela I, Lavelle D, Ahmed M, et al. Regulation of myeloma cell growth through Akt/Gsk3/forkhead signaling pathway. Biochem Biophys Res Commun. 2002;297(4):760-4.
74. Faridi J, Fawcett J, Wang L, Roth RA. Akt promotes increased mammalian cell size by stimulating protein synthesis and inhibiting protein degradation. Am J Physiol Endocrinol Metab. 2003;285(5):E964-72.
75. Latronico MV, Costinean S, Lavitrano ML, Peschle C, Condorelli G. Regulation of cell size and contractile function by AKT in cardiomyocytes. Ann N Y Acad Sci. 2004;1015:250-60.
76. Mourani PM, Garl PJ, Wenzlau JM, Carpenter TC, Stenmark KR, Weiser-Evans MC. Unique, highly proliferative growth phenotype expressed by embryonic and neointimal smooth muscle cells is driven by constitutive Akt, mTOR, and p70S6K signaling and is actively repressed by PTEN. Circulation. 2004;109(10):1299-306.
77. Desmots F, Rissel M, Gilot D, Lagadic-Gossmann D, Morel F, Guguen-Guillouzo C, et al. Pro-inflammatory cytokines tumor necrosis factor alpha and interleukin-6 and survival factor epidermal growth factor positively regulate the murine GSTA4 enzyme in hepatocytes. J Biol Chem. 2002;277(20):17892-900.
78. Osawa Y, Banno Y, Nagaki M, Brenner DA, Naiki T, Nozawa Y, et al. TNF-alpha-induced sphingosine 1-phosphate inhibits apoptosis through a phosphatidylinositol 3-kinase/Akt pathway in human hepatocytes. J Immunol. 2001;167(1):173-80.
79. Puri KD, Doggett TA, Huang CY, Douangpanya J, Hayflick JS, Turner M, et al. The role of endothelial PI3Kgamma activity in neutrophil trafficking. Blood. 2005;106(1):150-7.
80. Munugalavadla V, Borneo J, Ingram DA, Kapur R. p85alpha subunit of class IA PI-3 kinase is crucial for macrophage growth and migration. Blood. 2005;106(1):103-9.
81. Koniaris LG, McKillop IH, Schwartz SI, Zimmers TA. Liver regeneration. J Am Coll Surg. 2003;197(4):634-59.
82. Vanhaesebroeck B, Waterfield MD. Signaling by distinct classes of phosphoinositide 3-kinases. Exp Cell Res. 1999;253(1):239-54.
83. Fresno Vara JA, Casado E, de Castro J, Cejas P, Belda-Iniesta C, Gonzalez-Baron M. PI3K/Akt signalling pathway and cancer. Cancer Treat Rev. 2004;30(2):193-204.
84. Duronio V. The life of a cell: apoptosis regulation by the PI3K/PKB pathway. Biochem J. 2008;415(3):333-44.
85. Oudit GY, Sun H, Kerfant BG, Crackower MA, Penninger JM, Backx PH. The role of phosphoinositide-3 kinase and PTEN in cardiovascular physiology and disease. J Mol Cell Cardiol. 2004;37(2):449-71.
86. Alessi DR, James SR, Downes CP, Holmes AB, Gaffney PR, Reese CB, et al. Characterization of a 3-phosphoinositide-dependent protein kinase which phosphorylates and activates protein kinase Balpha. Curr Biol. 1997;7(4):261-9.
87. Andjelkovic M, Alessi DR, Meier R, Fernandez A, Lamb NJ, Frech M, et al. Role of translocation in the activation and function of protein kinase B. J Biol Chem. 1997;272(50):31515-24.
88. Franke TF, Kaplan DR, Cantley LC, Toker A. Direct regulation of the Akt proto-oncogene product by phosphatidylinositol-3,4-bisphosphate. Science. 1997;275(5300):665-8.
89. Alessi DR, Andjelkovic M, Caudwell B, Cron P, Morrice N, Cohen P, et al. Mechanism of activation of protein kinase B by insulin and IGF-1. EMBO J. 1996;15(23):6541-51.
90. Matheny RW Jr, Adamo ML. Current perspectives on Akt Aktivation and Akt-ions. Exp Biol Med (Maywood). 2009;234(11):1264-70.
91. Stokoe D, Stephens LR, Copeland T, Gaffney PR, Reese CB, Painter GF, et al. Dual role of phosphatidylinositol-3,4,5-trisphosphate in the activation of protein kinase B. Science. 1997;277(5325):567-70.
92. Fingar DC, Salama S, Tsou C, Harlow E, Blenis J. Mammalian cell size is controlled by mTOR and its downstream targets S6K1 and 4EBP1/eIF4E. Genes Dev. 2002;16(12):1472-87.
93. Hay N, Sonenberg N. Upstream and downstream of mTOR. Genes Dev. 2004;18(16):1926-45.
94. Ruvinsky I, Meyuhas O. Ribosomal protein S6 phosphorylation: from protein synthesis to cell size. Trends Biochem Sci. 2006;31(6):342-8.
95. Haga S, Ogawa W, Inoue H, Terui K, Ogino T, Igarashi R, et al. Compensatory recovery of liver mass by Akt-mediated hepatocellular hypertrophy in liver-specific STAT3-deficient mice. J Hepatol. 2005;43(5):799-807.
96. Collins BJ, Deak M, Arthur JS, Armit LJ, Alessi DR. In vivo role of the PIF-binding docking site of PDK1 defined by knockin mutation. EMBO J. 2003;22(16):4202-11.
97. Haga S, Ozaki M, Inoue H, Okamoto Y, Ogawa W, Takeda K, et al. The survival pathways phosphatidylinositol-3 kinase (PI3- K)/phosphoinositide- dependent protein kinase 1 (PDK1)/Akt modulate liver regeneration through hepatocyte size rather than proliferation. Hepatology. 2009;49(1):204-14.
98. Stiles B, Wang Y, Stahl A, Bassilian S, Lee WP, Kim YJ, et al. Liver-specific deletion of negative regulator Pten results in fatty liver and insulin hypersensitivity [corrected]. Proc Natl Acad Sci USA. 2004;101(7):2082-7.
99. Mullany LK, Nelsen CJ, Hanse EA, Goggin MM, Anttila CK, Peterson M, et al. Akt-mediated liver growth promotes induction of cyclin E through a novel translational mechanism and a p21-mediated cell cycle arrest. J Biol Chem. 2007;282(29):21244-52.
100. Jackson LN, Larson SD, Silva SR, Rychahou PG, Chen LA, Qiu S, et al. PI3K/Akt activation is critical for early hepatic regeneration after partial hepatectomy. Am J Physiol Gastrointest Liver Physiol. 2008;294(6):G1401-10.