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Pathological implications of cadherin zonation in mouse liver

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Abstract

Both acute and chronic liver diseases are associated with ample re-modeling of the liver parenchyma leading to functional impairment, which is thus obviously the cause or the consequence of the disruption of the epithelial integrity. It was, therefore, the aim of this study to investigate the distribution of the adherens junction components E- and N-cadherin, which are important determinants of tissue cohesion. E-cadherin was expressed in periportal but not in perivenous hepatocytes. In contrast, N-cadherin was more enriched towards the perivenous hepatocytes. In agreement, β-catenin, which links both cadherins via α-catenin to the actin cytoskeleton, was expressed ubiquitously. This zonal expression of cadherins was preserved in acute liver injury after treatment with acetaminophen or partial hepatectomy, but disrupted in chronic liver damage like in non-alcoholic steatohepatitis (NASH) or α1-antitrypsin deficiency. Hepatocyte proliferation during acetaminophen-induced liver damage was predominant at the boundary between the damaged perivenous and the intact periportal parenchyma indicating a minor contribution of periportal hepatocytes to liver regeneration. In NASH livers, an oval cell reaction was observed pointing to massive tissue damage coinciding with the gross impairment of hepatocyte proliferation. In the liver parenchyma, metabolic functions are distributed heterogeneously. For example, the expression of phosphoenolpyruvate carboxykinase and E-cadherin overlapped in periportal hepatocytes. Thus, during liver regeneration after acute damage, the intact periportal parenchyma might sustain essential metabolic support like glucose supply or ammonia detoxification. However, disruption of epithelial integrity during chronic challenges may increase susceptibility to metabolic liver diseases such as NASH or vice versa. This might suggest the regulatory integration of tissue cohesion and metabolic functions in the liver.

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References

  1. Colnot SPC (2011) Liver zonation. In: Monga SPS (ed) Molecular pathology of liver diseases, vol 5. Molecular Pathology Library, Springer, pp 7–16. doi:10.1007/978-1-4419-7107-4

  2. Jungermann K, Katz N (1989) Functional specialization of different hepatocyte populations. Physiol Rev 69(3):708–764

    CAS  PubMed  Google Scholar 

  3. Jungermann K, Kietzmann T (2000) Oxygen: modulator of metabolic zonation and disease of the liver. Hepatology 31(2):255–260. doi:10.1002/hep.510310201

    Article  CAS  PubMed  Google Scholar 

  4. Brosnan ME, Brosnan JT (2009) Hepatic glutamate metabolism: a tale of 2 hepatocytes. Am J Clin Nutr 90(3):857S–861S. doi:10.3945/ajcn.2009.27462Z

    Article  CAS  PubMed  Google Scholar 

  5. Benhamouche S, Decaens T, Godard C, Chambrey R, Rickman DS, Moinard C, Vasseur-Cognet M, Kuo CJ, Kahn A, Perret C, Colnot S (2006) Apc tumor suppressor gene is the “zonation-keeper” of mouse liver. Dev Cell 10(6):759–770. doi:10.1016/j.devcel.2006.03.015

    Article  CAS  PubMed  Google Scholar 

  6. Burke ZD, Reed KR, Phesse TJ, Sansom OJ, Clarke AR, Tosh D (2009) Liver zonation occurs through a beta-catenin-dependent, c-Myc-independent mechanism. Gastroenterology 136(7):2316–2324. doi:10.1053/j.gastro.2009.02.063 (e2311–2313)

    Article  CAS  PubMed  Google Scholar 

  7. Apte U, Zeng G, Thompson MD, Muller P, Micsenyi A, Cieply B, Kaestner KH, Monga SP (2007) Beta-catenin is critical for early postnatal liver growth. Am J Physiol Gastrointest Liver Physiol 292(6):G1578–G1585. doi:10.1152/ajpgi.00359.2006

    Article  CAS  PubMed  Google Scholar 

  8. Thompson MD, Capra V, Takasaki J, Maresca G, Rovati GE, Slutsky AS, Lilly C, Zamel N, McIntyre Burnham W, Cole DE, Siminovitch KA (2007) A functional G300S variant of the cysteinyl leukotriene 1 receptor is associated with atopy in a Tristan da Cunha isolate. Pharmacogenet Genomics 17(7):539–549. doi:10.1097/FPC.0b013e328012d0bf

    Article  CAS  PubMed  Google Scholar 

  9. Ray JG, Thompson MD, Vermeulen MJ, Meier C, Wyatt PR, Wong PY, Summers AM, Farrell SA, Cole DE (2007) Metabolic syndrome features and risk of neural tube defects. BMC Pregnancy Childbirth 7:21. doi:10.1186/1471-2393-7-21

    Article  PubMed  PubMed Central  Google Scholar 

  10. Traweger A, Toepfer S, Wagner RN, Zweimueller-Mayer J, Gehwolf R, Lehner C, Tempfer H, Krizbai I, Wilhelm I, Bauer HC, Bauer H (2013) Beyond cell–cell adhesion: emerging roles of the tight junction scaffold ZO-2. Tissue Barriers 1(2):e25039. doi:10.4161/tisb.25039

    Article  PubMed  PubMed Central  Google Scholar 

  11. You H, Lei P, Andreadis ST (2013) JNK is a novel regulator of intercellular adhesion. Tissue Barriers 1(5):e26845. doi:10.4161/tisb.26845

    Article  PubMed  PubMed Central  Google Scholar 

  12. Lindner I, Hemdan NY, Buchold M, Huse K, Bigl M, Oerlecke I, Ricken A, Gaunitz F, Sack U, Naumann A, Hollborn M, Thal D, Gebhardt R, Birkenmeier G (2010) Alpha2-macroglobulin inhibits the malignant properties of astrocytoma cells by impeding beta-catenin signaling. Cancer Res 70(1):277–287. doi:10.1158/0008-5472.CAN-09-1462

    Article  CAS  PubMed  Google Scholar 

  13. Gumbiner BM (2005) Regulation of cadherin-mediated adhesion in morphogenesis. Nat Rev Mol Cell Biol 6(8):622–634. doi:10.1038/nrm1699

    Article  CAS  PubMed  Google Scholar 

  14. Halbleib JM, Nelson WJ (2006) Cadherins in development: cell adhesion, sorting, and tissue morphogenesis. Genes Dev 20(23):3199–3214. doi:10.1101/gad.1486806

    Article  CAS  PubMed  Google Scholar 

  15. Sekine S, Ogawa R, McManus MT, Kanai Y, Hebrok M (2009) Dicer is required for proper liver zonation. J Pathol 219(3):365–372. doi:10.1002/path.2606

    Article  CAS  PubMed  Google Scholar 

  16. Riehle KJ, Dan YY, Campbell JS, Fausto N (2011) New concepts in liver regeneration. J Gastroenterol Hepatol 26(Suppl 1):203–212. doi:10.1111/j.1440-1746.2010.06539.x

    Article  PubMed  PubMed Central  Google Scholar 

  17. Hadem J, Tacke F, Bruns T, Langgartner J, Strnad P, Denk GU, Fikatas P, Manns MP, Hofmann WP, Gerken G, Grunhage F, Umgelter A, Trautwein C, Canbay A (2012) Etiologies and outcomes of acute liver failure in Germany. Clin Gastroenterol Hepatol 10(6):664–669. doi:10.1016/j.cgh.2012.02.016 (e662)

    Article  PubMed  Google Scholar 

  18. Lee WM, Stravitz RT, Larson AM (2012) Introduction to the revised American Association for the Study of Liver Diseases Position Paper on acute liver failure 2011. Hepatology 55(3):965–967. doi:10.1002/hep.25551

    Article  PubMed  PubMed Central  Google Scholar 

  19. Stravitz RT, Kramer AH, Davern T, Shaikh AO, Caldwell SH, Mehta RL, Blei AT, Fontana RJ, McGuire BM, Rossaro L, Smith AD, Lee WM (2007) Intensive care of patients with acute liver failure: recommendations of the US. Acute Liver Failure Study Group. Crit Care Med 35(11):2498–2508. doi:10.1097/01.CCM.0000287592.94554.5F

    Article  PubMed  Google Scholar 

  20. Lee WM (2012) Recent developments in acute liver failure. Best Pract Res Clin Gastroenterol 26(1):3–16. doi:10.1016/j.bpg.2012.01.014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Younossi ZM (2008) Review article: current management of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis. Aliment Pharmacol Ther 28(1):2–12. doi:10.1111/j.1365-2036.2008.03710.x

    Article  CAS  PubMed  Google Scholar 

  22. Charlton MR, Burns JM, Pedersen RA, Watt KD, Heimbach JK, Dierkhising RA (2011) Frequency and outcomes of liver transplantation for nonalcoholic steatohepatitis in the United States. Gastroenterology 141(4):1249–1253. doi:10.1053/j.gastro.2011.06.061

    Article  PubMed  Google Scholar 

  23. Brunt EM (2004) Nonalcoholic steatohepatitis. Semin Liver Dis 24(1):3–20. doi:10.1055/s-2004-823098

    Article  PubMed  Google Scholar 

  24. Targher G, Day CP, Bonora E (2010) Risk of cardiovascular disease in patients with nonalcoholic fatty liver disease. N Engl J Med 363(14):1341–1350. doi:10.1056/NEJMra0912063

    Article  CAS  PubMed  Google Scholar 

  25. Ratziu V, Bellentani S, Cortez-Pinto H, Day C, Marchesini G (2010) A position statement on NAFLD/NASH based on the EASL 2009 special conference. J Hepatol 53(2):372–384. doi:10.1016/j.jhep.2010.04.008

    Article  PubMed  Google Scholar 

  26. Ekstedt M, Franzen LE, Mathiesen UL, Thorelius L, Holmqvist M, Bodemar G, Kechagias S (2006) Long-term follow-up of patients with NAFLD and elevated liver enzymes. Hepatology 44(4):865–873. doi:10.1002/hep.21327

    Article  CAS  PubMed  Google Scholar 

  27. Pan JJ, Fallon MB (2014) Gender and racial differences in nonalcoholic fatty liver disease. World J Hepatol 6(5):274–283. doi:10.4254/wjh.v6.i5.274

    Article  PubMed  PubMed Central  Google Scholar 

  28. Kucukoglu O, Guldiken N, Chen Y, Usachov V, El-Heliebi A, Haybaeck J, Denk H, Trautwein C, Strnad P (2014) High-fat diet triggers Mallory-Denk body formation through misfolding and crosslinking of excess keratin 8. Hepatology 60(1):169–178. doi:10.1002/hep.27068

    Article  CAS  PubMed  Google Scholar 

  29. Pelz S, Stock P, Bruckner S, Christ B (2012) A methionine-choline-deficient diet elicits NASH in the immunodeficient mouse featuring a model for hepatic cell transplantation. Exp Cell Res 318(3):276–287. doi:10.1016/j.yexcr.2011.11.005

    Article  CAS  PubMed  Google Scholar 

  30. Carlson JA, Rogers BB, Sifers RN, Finegold MJ, Clift SM, DeMayo FJ, Bullock DW, Woo SL (1989) Accumulation of PiZ alpha 1-antitrypsin causes liver damage in transgenic mice. J Clin Invest 83(4):1183–1190. doi:10.1172/JCI113999

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Rudnick DA, Liao Y, An JK, Muglia LJ, Perlmutter DH, Teckman JH (2004) Analyses of hepatocellular proliferation in a mouse model of alpha-1-antitrypsin deficiency. Hepatology 39(4):1048–1055. doi:10.1002/hep.20118

    Article  CAS  PubMed  Google Scholar 

  32. Stock P, Bruckner S, Winkler S, Dollinger MM, Christ B (2014) Human bone marrow mesenchymal stem cell-derived hepatocytes improve the mouse liver after acute acetaminophen intoxication by preventing progress of injury. Int J Mol Sci 15(4):7004–7028. doi:10.3390/ijms15047004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Strnad P, Zhou Q, Hanada S, Lazzeroni LC, Zhong BH, So P, Davern TJ, Lee WM, Omary MB (2010) Keratin variants predispose to acute liver failure and adverse outcome: race and ethnic associations. Gastroenterology 139(3):828–835. doi:10.1053/j.gastro.2010.06.007 (835, e821–823)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Martins PN, Theruvath TP, Neuhaus P (2008) Rodent models of partial hepatectomies. Liver Int 28(1):3–11. doi:10.1111/j.1478-3231.2007.01628.x

    Article  PubMed  Google Scholar 

  35. Anty R, Lemoine M (2011) Liver fibrogenesis and metabolic factors. Clin Res Hepatol Gastroenterol 35(Suppl 1):S10–S20. doi:10.1016/S2210-7401(11)70003-1

    Article  CAS  PubMed  Google Scholar 

  36. Takaki A, Kawai D, Yamamoto K (2013) Multiple hits, including oxidative stress, as pathogenesis and treatment target in non-alcoholic steatohepatitis (NASH). Int J Mol Sci 14(10):20704–20728. doi:10.3390/ijms141020704

    Article  PubMed  PubMed Central  Google Scholar 

  37. Vonghia L, Michielsen P, Francque S (2013) Immunological mechanisms in the pathophysiology of non-alcoholic steatohepatitis. Int J Mol Sci 14(10):19867–19890. doi:10.3390/ijms141019867

    Article  PubMed  PubMed Central  Google Scholar 

  38. Aurich H, Sgodda M, Kaltwasser P, Vetter M, Weise A, Liehr T, Brulport M, Hengstler JG, Dollinger MM, Fleig WE, Christ B (2009) Hepatocyte differentiation of mesenchymal stem cells from human adipose tissue in vitro promotes hepatic integration in vivo. Gut 58(4):570–581. doi:10.1136/gut.2008.154880

    Article  CAS  PubMed  Google Scholar 

  39. Ueberham E, Bottger J, Ueberham U, Grosche J, Gebhardt R (2010) Response of sinusoidal mouse liver cells to choline-deficient ethionine-supplemented diet. Comp Hepatol 9:8. doi:10.1186/1476-5926-9-8

    Article  PubMed  PubMed Central  Google Scholar 

  40. Straub BK, Rickelt S, Zimbelmann R, Grund C, Kuhn C, Iken M, Ott M, Schirmacher P, Franke WW (2011) E–N-cadherin heterodimers define novel adherens junctions connecting endoderm-derived cells. J Cell Biol 195(5):873–887. doi:10.1083/jcb.201106023

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Butz S, Larue L (1995) Expression of catenins during mouse embryonic development and in adult tissues. Cell Adhes Commun 3(4):337–352

    Article  CAS  PubMed  Google Scholar 

  42. Greve KW, Bianchini KJ, Stickle TR, Love JM, Doane BM, Thompson MD (2007) Effects of a community toxic release on the psychological status of children. Child Psychiatry Hum Dev 37(4):307–323. doi:10.1007/s10578-006-0036-3

    Article  PubMed  Google Scholar 

  43. Capra V, Thompson MD, Sala A, Cole DE, Folco G, Rovati GE (2007) Cysteinyl-leukotrienes and their receptors in asthma and other inflammatory diseases: critical update and emerging trends. Med Res Rev 27(4):469–527. doi:10.1002/med.20071

    Article  CAS  PubMed  Google Scholar 

  44. Gouw AS, Clouston AD, Theise ND (2011) Ductular reactions in human liver: diversity at the interface. Hepatology 54(5):1853–1863. doi:10.1002/hep.24613

    Article  PubMed  Google Scholar 

  45. Roskams TA, Theise ND, Balabaud C, Bhagat G, Bhathal PS, Bioulac-Sage P, Brunt EM, Crawford JM, Crosby HA, Desmet V, Finegold MJ, Geller SA, Gouw AS, Hytiroglou P, Knisely AS, Kojiro M, Lefkowitch JH, Nakanuma Y, Olynyk JK, Park YN, Portmann B, Saxena R, Scheuer PJ, Strain AJ, Thung SN, Wanless IR, West AB (2004) Nomenclature of the finer branches of the biliary tree: canals, ductules, and ductular reactions in human livers. Hepatology 39(6):1739–1745. doi:10.1002/hep.20130

    Article  PubMed  Google Scholar 

  46. Kietzmann T, Immenschuh S, Katz N, Jungermann K, Muller-Eberhard U (1995) Modulation of hemopexin gene expression by physiological oxygen tensions in primary rat hepatocyte cultures. Biochem Biophys Res Commun 213(2):397–403 (pii: S0006291X85721456)

    Article  CAS  PubMed  Google Scholar 

  47. Hespeling U, Jungermann K, Puschel GP (1995) Feedback-inhibition of glucagon-stimulated glycogenolysis in hepatocyte/Kupffer cell cocultures by glucagon-elicited prostaglandin production in Kupffer cells. Hepatology 22(5):1577–1583 (pii: S0270913995004113)

    CAS  PubMed  Google Scholar 

  48. Gebhardt R, Matz-Soja M (2014) Liver zonation: novel aspects of its regulation and its impact on homeostasis. World J Gastroenterol 20(26):8491–8504. doi:10.3748/wjg.v20.i26.8491

    Article  PubMed  PubMed Central  Google Scholar 

  49. Monga SP (2011) Role of Wnt/beta-catenin signaling in liver metabolism and cancer. Int J Biochem Cell Biol 43(7):1021–1029. doi:10.1016/j.biocel.2009.09.001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Gumbiner BM (1993) Proteins associated with the cytoplasmic surface of adhesion molecules. Neuron 11(4):551–564

    Article  CAS  PubMed  Google Scholar 

  51. Hartsock A, Nelson WJ (2008) Adherens and tight junctions: structure, function and connections to the actin cytoskeleton. Biochim Biophys Acta 1778(3):660–669. doi:10.1016/j.bbamem.2007.07.012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Schmelz M, Schmid VJ, Parrish AR (2001) Selective disruption of cadherin/catenin complexes by oxidative stress in precision-cut mouse liver slices. Toxicol Sci 61(2):389–394

    Article  CAS  PubMed  Google Scholar 

  53. Wickline ED, Awuah PK, Behari J, Ross M, Stolz DB, Monga SP (2011) Hepatocyte gamma-catenin compensates for conditionally deleted beta-catenin at adherens junctions. J Hepatol 55(6):1256–1262. doi:10.1016/j.jhep.2011.03.014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Troxell ML, Gopalakrishnan S, McCormack J, Poteat BA, Pennington J, Garringer SM, Schneeberger EE, Nelson WJ, Marrs JA (2000) Inhibiting cadherin function by dominant mutant E-cadherin expression increases the extent of tight junction assembly. J Cell Sci 113(Pt 6):985–996

    CAS  PubMed  Google Scholar 

  55. Yap AS, Crampton MS, Hardin J (2007) Making and breaking contacts: the cellular biology of cadherin regulation. Curr Opin Cell Biol 19(5):508–514. doi:10.1016/j.ceb.2007.09.008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Puschel GP, Nolte A, Schieferdecker HL, Rothermel E, Gotze O, Jungermann K (1996) Inhibition of anaphylatoxin C3a- and C5a- but not nerve stimulation- or noradrenaline-dependent increase in glucose output and reduction of flow in Kupffer cell-depleted perfused rat livers. Hepatology 24(3):685–690. doi:10.1002/hep.510240335

    Article  CAS  PubMed  Google Scholar 

  57. Elamin E, Masclee A, Dekker J, Jonkers D (2014) Ethanol disrupts intestinal epithelial tight junction integrity through intracellular calcium-mediated Rho/ROCK activation. Am J Physiol Gastrointest Liver Physiol 306(8):G677–G685. doi:10.1152/ajpgi.00236.2013

    Article  CAS  PubMed  Google Scholar 

  58. Miele L, Valenza V, La Torre G, Montalto M, Cammarota G, Ricci R, Masciana R, Forgione A, Gabrieli ML, Perotti G, Vecchio FM, Rapaccini G, Gasbarrini G, Day CP, Grieco A (2009) Increased intestinal permeability and tight junction alterations in nonalcoholic fatty liver disease. Hepatology 49(6):1877–1887. doi:10.1002/hep.22848

    Article  CAS  PubMed  Google Scholar 

  59. Munukka E, Pekkala S, Wiklund P, Rasool O, Borra R, Kong L, Ojanen X, Cheng SM, Roos C, Tuomela S, Alen M, Lahesmaa R, Cheng S (2014) Gut-adipose tissue axis in hepatic fat accumulation in humans. J Hepatol 61(1):132–138. doi:10.1016/j.jhep.2014.02.020

    Article  CAS  PubMed  Google Scholar 

  60. Ulluwishewa D, Anderson RC, McNabb WC, Moughan PJ, Wells JM, Roy NC (2011) Regulation of tight junction permeability by intestinal bacteria and dietary components. J Nutr 141(5):769–776. doi:10.3945/jn.110.135657

    Article  CAS  PubMed  Google Scholar 

  61. Fausto N, Campbell JS, Riehle KJ (2006) Liver regeneration. Hepatology 43(2 Suppl 1):S45–S53. doi:10.1002/hep.20969

    Article  CAS  PubMed  Google Scholar 

  62. Michalopoulos GK (2013) Principles of liver regeneration and growth homeostasis. Compr Physiol 3(1):485–513. doi:10.1002/cphy.c120014

    PubMed  Google Scholar 

  63. Doi Y, Tamura S, Nammo T, Fukui K, Kiso S, Nagafuchi A (2007) Development of complementary expression patterns of E- and N-cadherin in the mouse liver. Hepatol Res 37(3):230–237. doi:10.1111/j.1872-034X.2007.00028.x

    Article  CAS  PubMed  Google Scholar 

  64. Behari J, Zeng G, Otruba W, Thompson MD, Muller P, Micsenyi A, Sekhon SS, Leoni L, Monga SP (2007) R-Etodolac decreases beta-catenin levels along with survival and proliferation of hepatoma cells. J Hepatol 46(5):849–857. doi:10.1016/j.jhep.2006.11.017

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Wei Y, Van Nhieu JT, Prigent S, Srivatanakul P, Tiollais P, Buendia MA (2002) Altered expression of E-cadherin in hepatocellular carcinoma: correlations with genetic alterations, beta-catenin expression, and clinical features. Hepatology 36(3):692–701. doi:10.1053/jhep.2002.35342

    Article  CAS  PubMed  Google Scholar 

  66. Prange W, Breuhahn K, Fischer F, Zilkens C, Pietsch T, Petmecky K, Eilers R, Dienes HP, Schirmacher P (2003) Beta-catenin accumulation in the progression of human hepatocarcinogenesis correlates with loss of E-cadherin and accumulation of p53, but not with expression of conventional WNT-1 target genes. J Pathol 201(2):250–259. doi:10.1002/path.1448

    Article  CAS  PubMed  Google Scholar 

  67. Matsumura T, Makino R, Mitamura K (2001) Frequent down-regulation of E-cadherin by genetic and epigenetic changes in the malignant progression of hepatocellular carcinomas. Clin Cancer Res 7(3):594–599

    CAS  PubMed  Google Scholar 

  68. Rao RK, Basuroy S, Rao VU, Karnaky KJ Jr, Gupta A (2002) Tyrosine phosphorylation and dissociation of occludin-ZO-1 and E-cadherin-beta-catenin complexes from the cytoskeleton by oxidative stress. Biochem J 368(Pt 2):471–481. doi:10.1042/BJ20011804

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Kim WD, Kim YW, Cho IJ, Lee CH, Kim SG (2012) E-cadherin inhibits nuclear accumulation of Nrf2: implications for chemoresistance of cancer cells. J Cell Sci 125(Pt 5):1284–1295. doi:10.1242/jcs.095422

    Article  CAS  PubMed  Google Scholar 

  70. Naidu S, Vijayan V, Santoso S, Kietzmann T, Immenschuh S (2009) Inhibition and genetic deficiency of p38 MAPK up-regulates heme oxygenase-1 gene expression via Nrf2. J Immunol 182(11):7048–7057. doi:10.4049/jimmunol.0900006

    Article  CAS  PubMed  Google Scholar 

  71. Kietzmann T, Gorlach A (2005) Reactive oxygen species in the control of hypoxia-inducible factor-mediated gene expression. Semin Cell Dev Biol 16(4–5):474–486. doi:10.1016/j.semcdb.2005.03.010

    Article  CAS  PubMed  Google Scholar 

  72. Dimova EY, Kietzmann T (2008) Metabolic, hormonal and environmental regulation of plasminogen activator inhibitor-1 (PAI-1) expression: lessons from the liver. Thromb Haemost 100(6):992–1006

    CAS  PubMed  Google Scholar 

  73. Day CP, Saksena S (2002) Non-alcoholic steatohepatitis: definitions and pathogenesis. J Gastroenterol Hepatol 17(Suppl 3):S377–S384

    Article  PubMed  Google Scholar 

  74. Koo SH, Flechner L, Qi L, Zhang X, Screaton RA, Jeffries S, Hedrick S, Xu W, Boussouar F, Brindle P, Takemori H, Montminy M (2005) The CREB coactivator TORC2 is a key regulator of fasting glucose metabolism. Nature 437(7062):1109–1111. doi:10.1038/nature03967

    Article  CAS  PubMed  Google Scholar 

  75. Osawa Y, Seki E, Kodama Y, Suetsugu A, Miura K, Adachi M, Ito H, Shiratori Y, Banno Y, Olefsky JM, Nagaki M, Moriwaki H, Brenner DA, Seishima M (2011) Acid sphingomyelinase regulates glucose and lipid metabolism in hepatocytes through AKT activation and AMP-activated protein kinase suppression. Faseb J 25(4):1133–1144. doi:10.1096/fj.10-168351

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Winnick JJ, An Z, Ramnanan CJ, Smith M, Irimia JM, Neal DW, Moore MC, Roach PJ, Cherrington AD (2011) Hepatic glycogen supercompensation activates AMP-activated protein kinase, impairs insulin signaling, and reduces glycogen deposition in the liver. Diabetes 60(2):398–407. doi:10.2337/db10-0592

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Kubo K, Sekine S, Saito M (2006) Induction of multidrug resistance-associated protein MRP3 in the liver of rats fed with docosahexaenoic acid. Biosci Biotechnol Biochem 70(7):1672–1680. doi:10.1271/bbb.60019

    Article  CAS  PubMed  Google Scholar 

  78. Peng GP, Sun W, Wu W, Sun Z, Tan XF, Li SP, Chen Z (2008) PD-L1 expression in circulating dendritic cells of patients with chronic hepatitis B. Zhejiang Da Xue Xue Bao Yi Xue Ban 37(4):364–372

    CAS  PubMed  Google Scholar 

  79. Shackelford DB, Shaw RJ (2009) The LKB1-AMPK pathway: metabolism and growth control in tumour suppression. Nat Rev Cancer 9(8):563–575. doi:10.1038/nrc2676

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Tan XD, Duan RS, Shi CW, Qu X (2008) Effect of dehydroepiandrosterone on cellular immune response in experimental autoimmune neuritis in Lewis rats. Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi 24(8):760–763

    CAS  PubMed  Google Scholar 

  81. Nollet EAMC (2013) Integrin and adhesion regulation of autophagy and mitophagy. In: Bailly Y (ed) Autophagy—a double-edged sword—cell survival or death? InTech, pp 1–22. doi:10.5772/55398

  82. Eneling K, Brion L, Pinto V, Pinho MJ, Sznajder JI, Mochizuki N, Emoto K, Soares-da-Silva P, Bertorello AM (2012) Salt-inducible kinase 1 regulates E-cadherin expression and intercellular junction stability. Faseb J 26(8):3230–3239. doi:10.1096/fj.12-205609

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

This study was supported by grants to B. Christ from the German Research Council (CH 109/15-1). Parts of the work presented in this paper were made possible by funding from the German Federal Ministry of Education and Research (BMBF, 1315883 and 315733). S. Winkler was supported through the eALTA Award 2010 (Talecris). C.M. Niessen is supported by the German Cancer Aid, DFG grants SFB829 A1 and SFB832 A3 and Köln Fortune.

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    Authors and Affiliations

    1. Applied Molecular Hepatology Lab, Department of Visceral, Transplantation, Thoracic and Vascular Surgery, University of Leipzig, Liebigstraße 21, 04103, Leipzig, Germany

      Madlen Hempel, Sandra Winkler, Ozlem Kucukoglu, Sandra Brückner & Bruno Christ

    2. Department of Dermatology, Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD) Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany

      Annika Schmitz & Carien Niessen

    3. Translational Centre for Regenerative Medicine (TRM), Universität Leipzig, Leipzig, Germany

      Ozlem Kucukoglu & Bruno Christ

    Authors
    1. Madlen Hempel
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    2. Annika Schmitz
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    3. Sandra Winkler
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    4. Ozlem Kucukoglu
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    5. Sandra Brückner
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    6. Carien Niessen
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    7. Bruno Christ
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    Corresponding author

    Correspondence to Bruno Christ.

    Additional information

    M. Hempel and A. Schmitz contributed equally to the work.

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    Hempel, M., Schmitz, A., Winkler, S. et al. Pathological implications of cadherin zonation in mouse liver. Cell. Mol. Life Sci. 72, 2599–2612 (2015). https://doi.org/10.1007/s00018-015-1861-y

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    • DOI: https://doi.org/10.1007/s00018-015-1861-y

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