title: Activation of peroxisome proliferator activated receptor alpha ameliorates ethanol mediated liver fibrosis in mice.
abstract: BACKGROUND
  Peroxisome proliferator activated receptor alpha (PPARα) ameliorates ethanol induced hepatic steatohepatitis. However, its role in alcoholic liver fibrosis has not been fully clarified. The aim of this study was to elucidate the effect and the molecular basis of PPARα in ethanol induced liver fibrosis in mice.
  
  
  METHODS
  C57BL/6J mice were fed with 4% ethanol-containing Lieber-DeCarli liquid diet for eight weeks, and intraperitoneal injected with 5% carbon tetrachloride (CCl4) for the last four weeks to induce alcoholic liver fibrosis. PPARα agonist WY14643 was administered to mice during the last couple of weeks. The effects of PPARα induction on liver histology, activation of hepatic stellate cells (HSCs), as well as hepatic expression of inflammatory and fibrogenic factors were assessed.
  
  
  RESULTS
  The ethanol plus CCl4 treated mice exhibited progressive liver injury including piecemeal necrosis of hepatocytes, severe inflammatory cells infiltration and bridging fibrosis. This was accompanied by down-regulated hepatic expression of PPARα and the protective cytokines adiponectin, heme oxygenase-1 and interleukin-10. Additionally, up-regulation of the proinflammatory cytokine tumor necrosis factor-alpha, as well as the profibrogenic genes osteopontin, transforming growth factor-beta 1, visfatin, phosphatidylinositol 3-kinase, matrix metalloproteinase-2 (MMP-2) and MMP-9 was observed. WY14643 treatment restored expression of cytokines altered by ethanol plus CCl4 treatment and concomitantly ameliorated the liver injury.
  
  
  CONCLUSIONS
  The present study provides evidence for the protective role of PPARα induction in ameliorating ethanol mediated fibrosis through mediation of inflammatory and fibrogenic factors.
authors: Department of Traditional and Western Medical Hepatology, Third Hospital of Hebei Medical University, Shijiazhuang, China. nanyuemin@163.com
authors: Yue-Min
authors: YM
authors: Nan
authors: Ling-Bo
authors: LB
authors: Kong
authors: Wei-Guang
authors: WG
authors: Ren
authors: Rong-Qi
authors: RQ
authors: Wang
authors: Jing-Hua
authors: JH
authors: Du
authors: Wen-Cong
authors: WC
authors: Li
authors: Su-Xian
authors: SX
authors: Zhao
authors: Yu-Guo
authors: YG
authors: Zhang
authors: Wen-Juan
authors: WJ
authors: Wu
authors: Hai-Ling
authors: HL
authors: Di
authors: Ya
authors: Y
authors: Li
authors: Jun
authors: J
authors: Yu
mesh_terms: D052242:Adiponectin / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D002251:Carbon Tetrachloride; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D000431:Ethanol; D005786:Gene Expression Regulation / Q000187:drug effects; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism; D055166:Hepatic Stellate Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D016753:Interleukin-10 / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D020782:Matrix Metalloproteinases / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D054409:Nicotinamide Phosphoribosyltransferase / Q000235:genetics / Q000378:metabolism; D053495:Osteopontin / Q000235:genetics / Q000378:metabolism; D047493:PPAR alpha / Q000235:genetics* / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
chemical_list: D052242:Adiponectin; C499919:Adipoq protein, mouse; D000924:Anticholesteremic Agents; D016207:Cytokines; C556062:IL10 protein, mouse; D047493:PPAR alpha; D011743:Pyrimidines; C506896:Spp1 protein, mouse; D053773:Transforming Growth Factor beta1; D014409:Tumor Necrosis Factor-alpha; D053495:Osteopontin; D016753:Interleukin-10; D000431:Ethanol; C006253:pirinixic acid; D002251:Carbon Tetrachloride; D051547:Heme Oxygenase-1; D054409:Nicotinamide Phosphoribosyltransferase; C495867:nicotinamide phosphoribosyltransferase, mouse; D020782:Matrix Metalloproteinases
references: PLoS One. 2010 Nov 22;5(11):e14073
references: 21124921
references: Cardiovasc Res. 2008 May 1;78(2):356-65
references: 18093986
references: World J Gastroenterol. 2004 Sep 1;10(17):2574-9
references: 15300910
references: World J Gastroenterol. 2010 Mar 21;16(11):1330-6
references: 20238399
references: World J Gastroenterol. 2005 Mar 28;11(12):1753-8
references: 15793858
references: J Hepatol. 2006 Aug;45(2):306-20
references: 16797773
references: Hepatology. 2000 Jan;31(1):149-59
references: 10613740
references: Lipids Health Dis. 2011 Dec 30;10:246
references: 22208561
references: Am J Gastroenterol. 2008 Nov;103(11):2747-56
references: 18721242
references: Eur J Pediatr Surg. 2008 Aug;18(4):224-9
references: 18704890
references: J Mol Endocrinol. 2001 Apr;26(2):107-17
references: 11241162
references: Hepatology. 2012 Sep;56(3):1108-16
references: 22488688
references: Pathol Int. 2008 Jan;58(1):64-8
references: 18067644
references: J Biol Chem. 2007 Jun 8;282(23):17078-89
references: 17405876
references: Histol Histopathol. 2010 Aug;25(8):1075-91
references: 20552556
references: Hepatology. 1991 May;13(5):815-9
references: 2029987
references: Hepatogastroenterology. 2007 Oct-Nov;54(79):2092-8
references: 18251166
references: World J Gastroenterol. 2004 Jan;10(1):77-81
references: 14695773
references: Hepatology. 2008 Aug;48(2):458-73
references: 18666257
references: Ger Med Sci. 2009 Jun 30;7:Doc05
references: 19675745
references: Hepatology. 2005 May;41(5):1074-84
references: 15841469
references: Arch Toxicol. 2009 Jun;83(6):519-48
references: 19448996
references: Hepatology. 2012 Feb;55(2):594-608
references: 21953216
references: Am J Pathol. 2005 Jun;166(6):1655-69
references: 15920151
references: J Hepatol. 2001 Aug;35(2):297-306
references: 11580156
references: Zhonghua Gan Zang Bing Za Zhi. 2010 Mar;18(3):163-6
references: 20698076
references: Hepatology. 2011 Aug;54(2):675-86
references: 21567435
references: J Immunol. 2006 Aug 15;177(4):2592-600
references: 16888021
references: Life Sci. 2011 Aug 1;89(5-6):204-12
references: 21718706
references: Clin Chim Acta. 1997 Jan 3;257(1):59-84
references: 9028626
references: J Biochem. 2011 Apr;149(4):405-14
references: 21288887
references: Am J Physiol Gastrointest Liver Physiol. 2006 May;290(5):G998-1007
references: 16410364
references: Liver Int. 2004 Oct;24(5):492-501
references: 15482348
references: Hepatology. 2008 Dec;48(6):2027-2039
references: 19003881
references: Biochem Biophys Res Commun. 2011 Jun 10;409(3):448-53
references: 21600192
references: J Free Radic Biol Med. 1985;1(1):27-38
references: 3915301
references: Gut. 2006 Mar;55(3):415-24
references: 16174657
references: Mol Pharm. 2009 May-Jun;6(3):772-9
references: 19388665
references: Hepatology. 1999 Jun;29(6):1760-7
references: 10347119
references: Lipids Health Dis. 2011 Feb 12;10:31
references: 21314960
references: Gene Ther. 2010 Jun;17(6):790-8
references: 20376096
references: J Biol Chem. 2007 Apr 27;282(17):12928-39
references: 17322299
references: World J Gastroenterol. 2004 Sep 15;10(18):2706-10
references: 15309723
references: Hepatology. 2011 Mar;53(3):935-44
references: 21374664