title: Hepatocellular proliferation correlates with inflammatory cell and cytokine changes in a murine model of nonalchoholic fatty liver disease.
abstract: Nonalchoholic fatty liver disease (NAFLD) is a problem of increasing prevalence and clinical significance worldwide and is associated with increased risk of development of end stage liver disease and cirrhosis, and can be complicated by hepatocellular carcinoma (HCC). NAFLD is characterized by physical and molecular changes in the liver microenvironment which include an influx of inflammatory cell populations, fibrosis, changes in gene expression, and cytokine production. To better understand changes to the liver in the setting of steatosis, we used a murine model of diet induced hepatic steatosis and corroborated our results with human patient samples of NAFLD. Among the cellular changes, we identified a significant increase in hepatocellular proliferation in the setting of steatosis as compared to controls. Analysis of inflammatory cell populations revealed increased infiltration of CD11b positive myeloid and CD3 positive lymphocytic cell populations in steatotic livers compared to normal livers. Resident Kupffer cells of the liver comprise the largest percentage of these myeloid cells and appear to be responsible for important cytokine alterations impacting proliferation of cells in the liver microenvironment. Significant alterations in cytokine profiles in the plasma and liver tissue lysates from normal and steatotic mice were detected including leptin, CXCL1, CXCL2, and CXCL16 that were further shown to directly increase hepatocyte proliferation in vitro. This increased hepatocellular proliferation and turnover in the setting of steatosis may play important roles in the progression and complications of NAFLD.
authors.affiliation: Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America ; Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America.
authors.forename: Michael N
authors.initials: MN
authors.lastname: Vansaun
authors.forename: Alisha M
authors.initials: AM
authors.lastname: Mendonsa
authors.forename: D
authors.initials: D
authors.lastname: Lee Gorden
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000378:metabolism* / Q000473:pathology*; D016207:Cytokines / Q000378:metabolism* / Q000494:pharmacology; D004195:Disease Models, Animal; D005234:Fatty Liver / Q000378:metabolism* / Q000473:pathology*; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007249:Inflammation / Q000378:metabolism* / Q000473:pathology*; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology; D008214:Lymphocytes / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D022423:Myeloid Cells / Q000378:metabolism / Q000473:pathology; D065626:Non-alcoholic Fatty Liver Disease
chemical_list: D016207:Cytokines
references.citation: Hepatology. 2009 May;49(5):1645-54
references.pmid: 19205030
references.citation: Am J Pathol. 2009 Jul;175(1):355-64
references.pmid: 19541928
references.citation: Physiol Res. 2001;50(2):183-9
references.pmid: 11522046
references.citation: Am J Respir Crit Care Med. 2008 Apr 1;177(7):771-80
references.pmid: 18187693
references.citation: Int J Oncol. 2007 Apr;30(4):803-11
references.pmid: 17332918
references.citation: Hepatology. 2010 Jun;51(6):1972-8
references.pmid: 20209604
references.citation: J Biol Chem. 2012 Nov 23;287(48):40161-72
references.pmid: 23066023
references.citation: Cancer Res. 2012 Dec 15;72(24):6338-43
references.pmid: 23222300
references.citation: Hepatology. 2001 Dec;34(6):1158-63
references.pmid: 11732005
references.citation: Shock. 1998 Oct;10(4):248-57
references.pmid: 9788656
references.citation: Eur Rev Med Pharmacol Sci. 2005 Sep-Oct;9(5):291-3
references.pmid: 16231592
references.citation: J Gastroenterol Hepatol. 2000 Nov;15(11):1325-32
references.pmid: 11129229
references.citation: Am J Respir Cell Mol Biol. 2006 Aug;35(2):175-81
references.pmid: 16543609
references.citation: Hepatology. 2006 Feb;43(2 Suppl 1):S99-S112
references.pmid: 16447287
references.citation: Clin Rev Allergy Immunol. 2009 Feb;36(1):4-12
references.pmid: 18600481
references.citation: Hepatology. 2013 Aug;58(2):589-602
references.pmid: 23322710
references.citation: PLoS One. 2010 Oct 22;5(10):e13577
references.pmid: 21042596
references.citation: Am J Physiol Gastrointest Liver Physiol. 2002 Aug;283(2):G256-65
references.pmid: 12121871
references.citation: Proc Natl Acad Sci U S A. 2010 Jul 20;107(29):13063-8
references.pmid: 20616008
references.citation: J Hepatol. 2006 Jan;44(1):197-208
references.pmid: 16274837
references.citation: Hepatology. 2004 Jul;40(1):46-54
references.pmid: 15239085
references.citation: Nat Clin Pract Endocrinol Metab. 2006 Jun;2(6):335-48
references.pmid: 16932311
references.citation: J Immunol. 2003 Sep 15;171(6):2797-803
references.pmid: 12960300
references.citation: Lab Invest. 2006 Nov;86(11):1161-71
references.pmid: 16983330
references.citation: J Hepatol. 2008 Apr;48(4):628-37
references.pmid: 18267346
references.citation: PLoS One. 2009 Nov 20;4(11):e7929
references.pmid: 19936233
references.citation: Antioxid Redox Signal. 2011 Sep 1;15(5):1325-65
references.pmid: 20969475
references.citation: Int J Clin Exp Pathol. 2010 Aug 02;3(7):675-80
references.pmid: 20830238
references.citation: Nat Rev Cancer. 2004 Aug;4(8):579-91
references.pmid: 15286738
references.citation: Gut. 2001 Oct;49(4):526-33
references.pmid: 11559650
references.citation: Mediators Inflamm. 2009;2009:831670
references.pmid: 19753129
references.citation: Gastroenterology. 2012 Apr;142(4):711-725.e6
references.pmid: 22326434
references.citation: Ann Surg Oncol. 2012 Jul;19 Suppl 3:S518-27
references.pmid: 21845497
references.citation: Gut. 2012 Mar;61(3):416-26
references.pmid: 21813474
references.citation: Am J Physiol Gastrointest Liver Physiol. 2012 Jan 1;302(1):G77-84
references.pmid: 21995961
references.citation: Lab Invest. 2010 Dec;90(12):1794-804
references.pmid: 20697377
references.citation: N Engl J Med. 2000 Nov 16;343(20):1467-76
references.pmid: 11078773
references.citation: J Hepatol. 2011 Jun;54(6):1195-204
references.pmid: 21145835
references.citation: Obes Surg. 2007 Oct;17(10):1374-80
references.pmid: 18000721
references.citation: Hepatology. 2003 Nov;38(5):1188-98
references.pmid: 14578857
references.citation: Cell Res. 2011 Jan;21(1):159-68
references.pmid: 21187858
references.citation: World J Gastroenterol. 2006 Dec 14;12(46):7413-20
references.pmid: 17167827
references.citation: Cell. 2010 Jan 22;140(2):197-208
references.pmid: 20141834
references.citation: World J Gastroenterol. 2012 Feb 28;18(8):727-35
references.pmid: 22371632
references.citation: Immunol Rev. 2000 Apr;174:160-71
references.pmid: 10807515
references.citation: Lab Invest. 2013 Jan;93(1):20-30
references.pmid: 23069937
references.citation: Science. 2011 Jun 24;332(6037):1519-23
references.pmid: 21700865
references.citation: J Clin Gastroenterol. 2006 Mar;40 Suppl 1:S17-29
references.pmid: 16540762
references.citation: World J Gastroenterol. 2005 Aug 28;11(32):4979-85
references.pmid: 16124049
references.citation: Infect Immun. 2005 Jul;73(7):4007-16
references.pmid: 15972488
references.citation: Clin Sci (Lond). 2012 Oct;123(7):459-71
references.pmid: 22545719
references.citation: Lab Invest. 2010 Aug;90(8):1169-78
references.pmid: 20368703
references.citation: Hepatology. 2010 May;51(5):1820-32
references.pmid: 20432259
references.citation: Am J Physiol Gastrointest Liver Physiol. 2012 Jun 1;302(11):G1310-21
references.pmid: 22442158
references.citation: FASEB J. 1999 Sep;13(12):1565-74
references.pmid: 10463948
references.citation: J Exp Med. 1996 Nov 1;184(5):1939-51
references.pmid: 8920881
references.citation: J Leukoc Biol. 2002 Jul;72(1):9-18
references.pmid: 12101257
references.citation: J Immunol. 2008 Oct 1;181(7):4656-65
references.pmid: 18802068