World J Hepatol. 2016 Feb 08;8(4):211-25. doi: 10.4254/wjh.v8.i4.211.
Lack of hepcidin expression attenuates steatosis and causes fibrosis in the liver.
World journal of hepatology
Sizhao Lu, Robert G Bennett, Kusum K Kharbanda, Duygu Dee Harrison-Findik
Affiliations
Affiliations
- Sizhao Lu, Robert G Bennett, Department of Biochemistry, University of Nebraska Medical Center, Omaha, NE 68198-5870, United States.
PMID: 26855692
PMCID: PMC4733464 DOI: 10.4254/wjh.v8.i4.211
Abstract
AIM: To investigate the role of key iron-regulatory protein, hepcidin in non-alcoholic fatty liver disease (NAFLD).
METHODS: Hepcidin (Hamp1) knockout and floxed control mice were administered a high fat and high sucrose (HFS) or a regular control diet for 3 or 7 mo. Steatosis, triglycerides, fibrosis, protein and gene expression in mice livers were determined by histological and biochemical techniques, western blotting and real-time polymerase chain reaction.
RESULTS: Knockout mice exhibited hepatic iron accumulation. Despite similar weight gains, HFS feeding induced hepatomegaly in floxed, but not knockout, mice. The livers of floxed mice exhibited higher levels of steatosis, triglycerides and c-Jun N-terminal kinase (JNK) phosphorylation than knockout mice. In contrast, a significant increase in fibrosis was observed in knockout mice livers within 3 mo of HFS administration. The hepatic gene expression levels of sterol regulatory element-binding protein-1c and fat-specific protein-27, but not peroxisome proliferator-activated receptor-alpha or microsomal triglyceride transfer protein, were attenuated in HFS-fed knockout mice. Knockout mice fed with regular diet displayed increased carnitine palmitoyltransferase-1a and phosphoenolpyruvate carboxykinase-1 but decreased glucose-6-phosphatase expression in the liver. In summary, attenuated steatosis correlated with decreased expression of lipogenic and lipid storage genes, and JNK phosphorylation. Deletion of Hamp1 alleles per se modulated hepatic expression of beta-oxidation and gluconeogenic genes.
CONCLUSION: Lack of hepcidin expression inhibits hepatic lipid accumulation and induces early development of fibrosis following high fat intake. Hepcidin and iron may play a role in the regulation of metabolic pathways in the liver, which has implications for NAFLD pathogenesis.
Keywords: Hamp; Iron; Metabolic genes; Non-alcoholic fatty liver disease; Non-alcoholic steatohepatitis; Steatohepatitis; Steatosis
References
- Am J Gastroenterol. 1999 Sep;94(9):2467-74 - PubMed
- Hepatology. 2011 Apr;53(4):1333-41 - PubMed
- Proc Natl Acad Sci U S A. 2003 Mar 18;100(6):3077-82 - PubMed
- Int J Mol Sci. 2013 Oct 15;14(10):20704-28 - PubMed
- Curr Opin Cell Biol. 1998 Apr;10(2):205-19 - PubMed
- Trends Endocrinol Metab. 2010 Dec;21(12):707-13 - PubMed
- Hepatology. 2010 Feb;51(2):679-89 - PubMed
- Curr Opin Lipidol. 2009 Apr;20(2):121-6 - PubMed
- Hepatology. 2011 Feb;53(2):448-57 - PubMed
- Hepatology. 2007 Dec;46(6):1979-85 - PubMed
- Am J Clin Nutr. 2008 May;87(5):1374-83 - PubMed
- Am J Physiol Gastrointest Liver Physiol. 2012 Jun 15;302(12):G1397-404 - PubMed
- Nat Rev Gastroenterol Hepatol. 2013 Nov;10(11):627-36 - PubMed
- Hepatology. 2007 Jun;45(6):1366-74 - PubMed
- World J Gastroenterol. 2012 Sep 14;18(34):4651-8 - PubMed
- Genes Nutr. 2012 Jul;7(3):415-25 - PubMed
- World J Gastroenterol. 2013 Feb 28;19(8):1158-65 - PubMed
- Eur J Biochem. 2004 Feb;271(3):462-9 - PubMed
- Blood. 2004 Apr 1;103(7):2816-21 - PubMed
- J Gastroenterol Hepatol. 2008 Nov;23(11):1635-48 - PubMed
- PLoS One. 2012;7(10 ):e48250 - PubMed
- J Hepatol. 2015 Mar;62(3):720-33 - PubMed
- World J Hepatol. 2015 Feb 27;7(2):177-88 - PubMed
- J Hepatol. 1997 Mar;26(3):584-92 - PubMed
- Hepatology. 2009 Jan;49(1):87-96 - PubMed
- Physiol Rev. 2013 Oct;93(4):1721-41 - PubMed
- Diabet Med. 2013 Dec;30(12):1495-9 - PubMed
- J Mol Med (Berl). 2009 Jul;87(7):679-95 - PubMed
- J Clin Invest. 2012 Oct;122(10 ):3529-40 - PubMed
- Dig Dis. 2010;28(1):247-54 - PubMed
- Mitochondrion. 2006 Feb;6(1):1-28 - PubMed
- J Biol Chem. 2001 Mar 16;276(11):7811-9 - PubMed
- Compr Physiol. 2014 Jan;4(1):177-97 - PubMed
- Blood. 2006 Aug 15;108(4):1402-5 - PubMed
- Br J Haematol. 2008 Sep;142(6):979-85 - PubMed
- Hepatology. 2006 Oct;44(4):865-73 - PubMed
- Transgenic Res. 2015 Aug;24(4):765-73 - PubMed
- Liver Int. 2006 Dec;26(10):1258-67 - PubMed
- Hepatology. 2011 Jul;54(1):273-84 - PubMed
- Histochem J. 1979 Jul;11(4):447-55 - PubMed
- Proc Natl Acad Sci U S A. 2010 Jun 15;107(24):10775-82 - PubMed
- Hepatol Int. 2012 Jan;6(1):332-41 - PubMed
- Gastroenterology. 2014 Apr;146(4):1060-9 - PubMed
- QJM. 2010 Feb;103(2):71-83 - PubMed
- Metab Syndr Relat Disord. 2011 Aug;9(4):287-90 - PubMed
- Hepatology. 2012 Nov;56(5):1730-40 - PubMed
- Biochim Biophys Acta. 2012 Sep;1823(9):1434-43 - PubMed
- Am J Gastroenterol. 2007 Jun;102(6):1251-8 - PubMed
- Proc Natl Acad Sci U S A. 2004 Aug 3;101(31):11245-50 - PubMed
- J Biol Chem. 2000 Oct 6;275(40):31078-85 - PubMed
- Lipids. 1978 Jul;13(7):473-8 - PubMed
- Horm Res Paediatr. 2013;80(1):11-7 - PubMed
- Int J Mol Sci. 2013 Nov 04;14(11):21833-57 - PubMed
- Clin Lipidol. 2011 Jun;6(3):293-303 - PubMed
- Hepatology. 2006 Jan;43(1):163-72 - PubMed
- Proc Natl Acad Sci U S A. 2001 Jul 17;98 (15):8780-5 - PubMed
- Gastroenterology. 2006 Sep;131(3):788-96 - PubMed
- Gastroenterology. 1998 Apr;114(4):842-5 - PubMed
- J Hepatol. 2014 Sep;61(3):633-41 - PubMed
- Mol Endocrinol. 2002 May;16(5):1013-28 - PubMed
- Annu Rev Pathol. 2010;5:145-71 - PubMed
- J Biol Chem. 1957 May;226(1):497-509 - PubMed
- J Nutr Biochem. 2013 Sep;24(9):1634-44 - PubMed
- Gastroenterology. 2010 Mar;138(3):905-12 - PubMed
- J Nutr. 1987 Sep;117(9):1514-9 - PubMed
- J Clin Invest. 2004 Jul;114(2):147-52 - PubMed
- Nat Rev Gastroenterol Hepatol. 2013 Jun;10(6):330-44 - PubMed
- Annu Rev Med. 2002;53:409-35 - PubMed
- J Nutr. 1978 Jan;108(1):152-62 - PubMed
- Science. 2004 Dec 17;306(5704):2090-3 - PubMed
- Annu Rev Pathol. 2011;6:425-56 - PubMed
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