Aryl Hydrocarbon Receptor Signaling Prevents Activation of Hepatic Stellate Cells and Liver Fibrogenesis in Mice.

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Abstrakt

Tytuł:: Aryl Hydrocarbon Receptor Signaling Prevents Activation of Hepatic Stellate Cells and Liver Fibrogenesis in Mice.
Autorzy:: Yan J; Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania.
Tung HC; Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania.
Li S; Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania.
Niu Y; Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania.
Garbacz WG; Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania.
Lu P; Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania.
Bi Y; Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania.
Li Y; Department of Pharmacy, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
He J; Department of Pharmacy, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
Xu M; Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania.
Ren S; Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania.
Monga SP; Department of Pathology and Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
Schwabe RF; Department of Medicine, Columbia University, New York, New York.
Yang D; Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania.
Xie W; Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania; Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania. Electronic address: .
Źródło:: Gastroenterology [Gastroenterology] 2019 Sep; Vol. 157 (3), pp. 793-806.e14. Date of Electronic Publication: 2019 Jun 03.
Typ publikacji:: Journal Article; Research Support, N.I.H., Extramural
Język:: English
Imprint Name(s):: Publication: Philadelphia, PA : W.B. Saunders
Original Publication: Baltimore.
MeSH Terms:: Cellular Senescence*/drug effects
Basic Helix-Loop-Helix Transcription Factors/*metabolism
Chemical and Drug Induced Liver Injury/*prevention & control
Hepatic Stellate Cells/*metabolism
Liver/*metabolism
Liver Cirrhosis, Experimental/*prevention & control
Receptors, Aryl Hydrocarbon/*metabolism
Animals ; Basic Helix-Loop-Helix Transcription Factors/agonists ; Basic Helix-Loop-Helix Transcription Factors/deficiency ; Basic Helix-Loop-Helix Transcription Factors/genetics ; Cell Proliferation ; Cells, Cultured ; Chemical and Drug Induced Liver Injury/genetics ; Chemical and Drug Induced Liver Injury/metabolism ; Chemical and Drug Induced Liver Injury/pathology ; Gene Expression Regulation ; Hepatic Stellate Cells/drug effects ; Hepatic Stellate Cells/pathology ; Indoles/pharmacology ; Liver/drug effects ; Liver/pathology ; Liver Cirrhosis, Experimental/genetics ; Liver Cirrhosis, Experimental/metabolism ; Liver Cirrhosis, Experimental/pathology ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Phenotype ; Receptors, Aryl Hydrocarbon/agonists ; Receptors, Aryl Hydrocarbon/deficiency ; Receptors, Aryl Hydrocarbon/genetics ; Signal Transduction ; Smad3 Protein/metabolism ; Thiazoles/pharmacology ; beta Catenin/metabolism
References:: Mol Cell Biol. 2013 May;33(10):2047-55. (PMID: 23508103)
Mol Cell. 2009 Nov 13;36(3):457-68. (PMID: 19917253)
Cell Metab. 2012 Nov 7;16(5):634-44. (PMID: 23140643)
Toxicol Res (Camb). 2015 Sep 1;4(5):1143-1158. (PMID: 26783425)
J Clin Invest. 2005 Feb;115(2):209-18. (PMID: 15690074)
Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15545-50. (PMID: 16199517)
Int J Exp Pathol. 2004 Oct;85(5):295-302. (PMID: 15379962)
Environ Health Perspect. 2017 Mar;125(3):428-436. (PMID: 27713108)
Toxicol Appl Pharmacol. 2016 Nov 15;311:42-51. (PMID: 27693115)
Prog Lipid Res. 2017 Jul;67:38-57. (PMID: 28606467)
Genes Dev. 2006 Mar 15;20(6):666-74. (PMID: 16543220)
Nature. 2007 Mar 29;446(7135):562-6. (PMID: 17392787)
Proc Natl Acad Sci U S A. 2002 Nov 12;99(23):14694-9. (PMID: 12409613)
Cell Metab. 2014 Dec 2;20(6):1076-87. (PMID: 25470552)
Nat Commun. 2013;4:2823. (PMID: 24264436)
Proc Natl Acad Sci U S A. 2005 Dec 6;102(49):17858-63. (PMID: 16301529)
Mol Endocrinol. 2015 Nov;29(11):1558-70. (PMID: 26407237)
Proc Natl Acad Sci U S A. 1996 Jun 25;93(13):6731-6. (PMID: 8692887)
BMC Genomics. 2011 Jul 15;12:365. (PMID: 21762485)
Science. 1995 May 5;268(5211):722-6. (PMID: 7732381)
Toxicol Sci. 2014 Jan;137(1):114-24. (PMID: 24154488)
J Biol Chem. 2010 Mar 19;285(12):8703-10. (PMID: 20097766)
Proc Natl Acad Sci U S A. 2009 Aug 11;106(32):13481-6. (PMID: 19651607)
Proc Natl Acad Sci U S A. 2012 Mar 20;109(12):4479-84. (PMID: 22392998)
J Toxicol Environ Health. 1989;27(2):165-71. (PMID: 2733058)
Hepatology. 2004 Jan;39(1):157-66. (PMID: 14752834)
Nat Rev Gastroenterol Hepatol. 2017 Jul;14(7):397-411. (PMID: 28487545)
Toxicol Appl Pharmacol. 2004 May 1;196(3):410-21. (PMID: 15094312)
Toxicology. 2011 Feb 4;280(1-2):10-7. (PMID: 21095216)
Crit Rev Eukaryot Gene Expr. 2008;18(3):207-50. (PMID: 18540824)
Nat Protoc. 2015 Feb;10(2):305-15. (PMID: 25612230)
Chem Res Toxicol. 2011 Apr 18;24(4):494-504. (PMID: 21370876)
Biochem Biophys Res Commun. 2001 Dec 21;289(5):1049-56. (PMID: 11741297)
Nat Commun. 2012 Mar 13;3:735. (PMID: 22415826)
Toxicol Sci. 2012 Dec;130(2):349-61. (PMID: 22903824)
Grant Information:: R01 DK083952 United States DK NIDDK NIH HHS; R01 ES023438 United States ES NIEHS NIH HHS; R35 ES030429 United States ES NIEHS NIH HHS
Contributed Indexing:: Keywords: Cell Type-Specific Effect; Gene Regulation; Signal Transduction; Xenobiotic Receptor
Substance Nomenclature:: 0 (2-(1'H-indole-3'-carbonyl)thiazole-4-carboxylic acid methyl ester)
0 (AHR protein, human)
0 (Ahr protein, mouse)
0 (Basic Helix-Loop-Helix Transcription Factors)
0 (CTNNB1 protein, mouse)
0 (Indoles)
0 (Receptors, Aryl Hydrocarbon)
0 (Smad3 Protein)
0 (Smad3 protein, mouse)
0 (Thiazoles)
0 (beta Catenin)
Entry Date(s):: Date Created: 20190607 Date Completed: 20190924 Latest Revision: 20210109
Update Code:: 20240105
PubMed Central ID:: PMC6707837
DOI:: 10.1053/j.gastro.2019.05.066
PMID:: 31170413
: Czasopismo naukowe

Background & Aims: The role of aryl hydrocarbon receptor (AhR) in liver fibrosis is controversial because loss and gain of AhR activity both lead to liver fibrosis. The goal of this study was to investigate how the expression of AhR by different liver cell types, hepatic stellate cells (HSCs) in particular, affects liver fibrosis in mice.
Methods: We studied the effects of AhR on primary mouse and human HSCs, measuring their activation and stimulation of fibrogenesis using RNA-sequencing analysis. C57BL/6J mice were given the AhR agonists 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) or 2-(1'H-indole-3'-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE); were given carbon tetrachloride (CCl 4 ); or underwent bile duct ligation. We also performed studies in mice with disruption of Ahr specifically in HSCs, hepatocytes, or Kupffer cells. Liver tissues were collected from mice and analyzed by histology, immunohistochemistry, and immunoblotting.
Results: AhR was expressed at high levels in quiescent HSCs, but the expression decreased with HSC activation. Activation of HSCs from AhR-knockout mice was accelerated compared with HSCs from wild-type mice. In contrast, TCDD or ITE inhibited spontaneous and transforming growth factor β-induced activation of HSCs. Mice with disruption of Ahr in HSCs, but not hepatocytes or Kupffer cells, developed more severe fibrosis after administration of CCl 4 or bile duct ligation. C57BL/6J mice given ITE did not develop CCl 4 -induced liver fibrosis, whereas mice without HSC AhR given ITE did develop CCl 4 -induced liver fibrosis. In studies of mouse and human HSCs, we found that AhR prevents transforming growth factor β-induced fibrogenesis by disrupting the interaction of Smad3 with β-catenin, which prevents the expression of genes that mediate fibrogenesis.
Conclusions: In studies of human and mouse HSCs, we found that AhR prevents HSC activation and expression of genes required for liver fibrogenesis. Development of nontoxic AhR agonists or strategies to activate AhR signaling in HSCs might be developed to prevent or treat liver fibrosis.
(Copyright © 2019 AGA Institute. Published by Elsevier Inc. All rights reserved.)

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