title: Age-related sensitivity to endotoxin-induced liver inflammation: Implication of inflammasome/IL-1β for steatohepatitis.
abstract: Aging is associated with increased vulnerability to inflammatory challenge. However, the effects of altered inflammatory response on the metabolic status of tissues or organs are not well documented. In this study, we present evidence demonstrating that lipopolysaccharide (LPS)-induced upregulation of the inflammasome/IL-1β pathway is accompanied with an increased inflammatory response and abnormal lipid accumulation in livers of aged rats. To monitor the effects of aging on LPS-induced inflammation, we administered LPS (2 mg kg(-1) ) to young (6-month old) and aged (24-month old) rats and found abnormal lipid metabolism in only aged rats with increased lipid accumulation in the liver. This lipid accumulation in the liver was due to the dysregulation of PPARα and SREBP1c. We also observed severe liver inflammation in aged rats as indicated by increased ALT levels in serum and increased Kupffer cells in the liver. Importantly, among many inflammation-associated factors, the aged rat liver showed chronically increased IL-1β production. Increased levels of IL-1β were caused by the upregulation of caspase-1 activity and inflammasome activation. In vitro studies with HepG2 cells demonstrated that treatment with IL-1β significantly induced lipid accumulation in hepatocytes through the regulation of PPARα and SREBP1c. In summary, we demonstrated that LPS-induced liver inflammation and lipid accumulation were associated with a chronically overactive inflammasome/IL-1β pathway in aged rat livers. Based on the present findings, we propose a mechanism of aging-associated progression of steatohepatitis induced by endotoxin, delineating a pathogenic role of the inflammasome/IL-1β pathway involved in lipid accumulation in the liver.
authors.affiliation: Molecular Inflammation Research Center for Aging Intervention (MRCA), College of Pharmacy, Pusan National University, Busan, Korea.
authors.forename: Ki Wung
authors.initials: KW
authors.lastname: Chung
authors.affiliation: Molecular Inflammation Research Center for Aging Intervention (MRCA), College of Pharmacy, Pusan National University, Busan, Korea.
authors.forename: Eun Kyeong
authors.initials: EK
authors.lastname: Lee
authors.affiliation: Molecular Inflammation Research Center for Aging Intervention (MRCA), College of Pharmacy, Pusan National University, Busan, Korea.
authors.forename: Dae Hyun
authors.initials: DH
authors.lastname: Kim
authors.affiliation: Molecular Inflammation Research Center for Aging Intervention (MRCA), College of Pharmacy, Pusan National University, Busan, Korea.
authors.forename: Hye Jin
authors.initials: HJ
authors.lastname: An
authors.affiliation: Molecular Inflammation Research Center for Aging Intervention (MRCA), College of Pharmacy, Pusan National University, Busan, Korea.
authors.forename: Nam Deuk
authors.initials: ND
authors.lastname: Kim
authors.affiliation: Molecular Inflammation Research Center for Aging Intervention (MRCA), College of Pharmacy, Pusan National University, Busan, Korea.
authors.forename: Dong Soon
authors.initials: DS
authors.lastname: Im
authors.affiliation: Molecular Inflammation Research Center for Aging Intervention (MRCA), College of Pharmacy, Pusan National University, Busan, Korea.
authors.forename: Jaewon
authors.initials: J
authors.lastname: Lee
authors.affiliation: Department of Physiology, The University of Texas Health Science Center at San Antonio, San Antonio, TX, 78229-3900, USA.
authors.forename: Byung Pal
authors.initials: BP
authors.lastname: Yu
authors.affiliation: Molecular Inflammation Research Center for Aging Intervention (MRCA), College of Pharmacy, Pusan National University, Busan, Korea.
authors.forename: Hae Young
authors.initials: HY
authors.lastname: Chung
mesh_terms: D000367:Age Factors; D000375:Aging / Q000235:genetics* / Q000276:immunology; D000410:Alanine Transaminase / Q000097:blood / Q000235:genetics; D000818:Animals; D020170:Caspase 1 / Q000235:genetics / Q000276:immunology; D005234:Fatty Liver / Q000139:chemically induced / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D005786:Gene Expression Regulation; D056945:Hep G2 Cells; D006801:Humans; D058847:Inflammasomes / Q000235:genetics* / Q000276:immunology; D053583:Interleukin-1beta / Q000235:genetics* / Q000276:immunology; D007728:Kupffer Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D050356:Lipid Metabolism / Q000235:genetics / Q000276:immunology; D008070:Lipopolysaccharides; D008099:Liver / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D008297:Male; D047493:PPAR alpha / Q000235:genetics* / Q000276:immunology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics* / Q000276:immunology
chemical_list: D058847:Inflammasomes; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D047493:PPAR alpha; D051780:Sterol Regulatory Element Binding Protein 1; D000410:Alanine Transaminase; D020170:Caspase 1
keywords: IL-1β; LPS; aging; inflammasome; inflammation; lipid accumulation
references.citation: Cell Metab. 2011 Jul 6;14(1):21-32
references.pmid: 21723501
references.citation: Hepatology. 2013 Jul;58(1):351-62
references.pmid: 23408710
references.citation: J Hepatol. 2012 Sep;57(3):642-54
references.pmid: 22634126
references.citation: Gut. 2014 Nov;63(11):1782-92
references.pmid: 24415562
references.citation: Hepatology. 2008 Sep;48(3):770-81
references.pmid: 18752326
references.citation: Nat Rev Gastroenterol Hepatol. 2013 Nov;10(11):627-36
references.pmid: 23958599
references.citation: J Am Aging Assoc. 2001 Oct;24(4):163-71
references.pmid: 23604881
references.citation: Mech Ageing Dev. 2003 Dec;124(10-12):1047-58
references.pmid: 14659593
references.citation: Crit Care Med. 2006 Jan;34(1):15-21
references.pmid: 16374151
references.citation: Hepatology. 2009 Jun;49(6):1877-87
references.pmid: 19291785
references.citation: Am J Physiol Gastrointest Liver Physiol. 2006 May;290(5):G852-8
references.pmid: 16603729
references.citation: Nat Immunol. 2012 Apr;13(4):333-42
references.pmid: 22430786
references.citation: Immun Ageing. 2013 Jun 06;10(1):21
references.pmid: 23742671
references.citation: Crit Care Med. 2009 Mar;37(3):1018-23
references.pmid: 19237912
references.citation: J Clin Invest. 2012 Oct;122(10):3476-89
references.pmid: 22945633
references.citation: Crit Care. 2012;16(5):235
references.pmid: 23134597
references.citation: J Pineal Res. 2011 Nov;51(4):416-25
references.pmid: 21689150
references.citation: Hepatology. 2014 Mar;59(3):898-910
references.pmid: 23813842
references.citation: PLoS Pathog. 2013;9(4):e1003330
references.pmid: 23633957
references.citation: Hepatology. 2010 Nov;52(5):1836-46
references.pmid: 21038418
references.citation: Anal Biochem. 1983 May;131(1):1-15
references.pmid: 6193725
references.citation: Nat Rev Immunol. 2009 Jan;9(1):57-62
references.pmid: 19104499
references.citation: J Clin Invest. 2009 Feb;119(2):305-14
references.pmid: 19164858
references.citation: Gastroenterology. 2010 Jul;139(1):323-34.e7
references.pmid: 20347818
references.citation: Gerontology. 2009;55(6):607-13
references.pmid: 19690397
references.citation: Hepatology. 2013 Mar;57(3):995-1004
references.pmid: 23081825
references.citation: Gastroenterology. 2011 Feb;140(2):697-708.e4
references.pmid: 20727895
references.citation: Cell Metab. 2012 May 2;15(5):635-45
references.pmid: 22560216
references.citation: Curr Opin Crit Care. 2011 Apr;17(2):153-9
references.pmid: 21346564
references.citation: Biochim Biophys Acta. 2008 Jul-Aug;1777(7-8):763-71
references.pmid: 18482575
references.citation: Hepatology. 2009 Jan;49(1):306-17
references.pmid: 19065650
references.citation: Clin Infect Dis. 2005 Nov 15;41 Suppl 7:S504-12
references.pmid: 16237654
references.citation: Physiol Rev. 2006 Apr;86(2):465-514
references.pmid: 16601267
references.citation: J Lipid Res. 1992 Dec;33(12):1765-76
references.pmid: 1479286
references.citation: Trends Endocrinol Metab. 2014 Jun;25(6):312-9
references.pmid: 24698032
references.citation: Curr Opin Lipidol. 1994 Jun;5(3):207-15
references.pmid: 7952915