title: Inhibition of Glutaminyl Cyclases alleviates CCL2-mediated inflammation of non-alcoholic fatty liver disease in mice.
abstract: Inflammation is an integral part of non-alcoholic fatty liver disease (NAFLD), the most prevalent form of hepatic pathology found in the general population. In this context, recently we have examined the potential role of Glutaminyl Cyclases (QC and isoQC), and their inhibitors, in the maturation of chemokines, for example, monocyte chemoattractant protein 1 (MCP-1, CCL2), to generate their bioactive conformation. Catalysis by isoQC leads to the formation of an N-terminal pyroglutamate residue protecting CCL2 against degradation by aminopeptidases. This is of importance because truncated forms possess a reduced potential to attract immune cells. Since liver inflammation is characterized by the up-regulation of different chemokine pathways, and within this CCL2 is known to be a prominent example, we hypothesised that application of QC/isoQC inhibitors may alleviate liver inflammation by destabilizing CCL2. Therefore, we investigated the role of QC/isoQC inhibition, in comparison with the angiotensin receptor blocker Telmisartan, during development of pathology in a mouse model of non-alcoholic fatty liver disease. Application of a QC/isoQC inhibitor led to a significant reduction in circulating alanine aminotransferase and NAFLD activity score accompanied by an inhibitory effect on hepatocyte ballooning. Further analysis revealed a specific reduction of inflammation by decreasing the number of F4/80-positive macrophages, which is in agreement with the proposed CCL2-related mechanism of action of QC/isoQC inhibitors. Finally, QC/isoQC inhibitor application attenuated liver fibrosis as characterized by reduced collagen deposition in the liver parenchyma. Thus in conclusion, QC/isoQC inhibitors are a promising novel class of anti-non-alcoholic steatohepatitis drugs which have a comparable disease-modifying effect to that of Telmisartan, which is probably mediated via specific interference with a comparable monocyte/macrophage infiltration that occurs under inflammatory conditions.
authors.affiliation: Probiodrug AG, Halle, Germany. holger.cynis@me.com
authors.forename: Holger
authors.initials: H
authors.lastname: Cynis
authors.forename: Astrid
authors.initials: A
authors.lastname: Kehlen
authors.forename: Monique
authors.initials: M
authors.lastname: Haegele
authors.forename: Torsten
authors.initials: T
authors.lastname: Hoffmann
authors.forename: Ulrich
authors.initials: U
authors.lastname: Heiser
authors.forename: Masato
authors.initials: M
authors.lastname: Fujii
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Shibazaki
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Yoneyama
authors.forename: Stephan
authors.initials: S
authors.lastname: Schilling
authors.forename: Hans-Ulrich
authors.initials: HU
authors.lastname: Demuth
mesh_terms: D019881:Aminoacyltransferases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology; D001565:Benzoates / Q000494:pharmacology; D045744:Cell Line, Tumor; D018932:Chemokine CCL2 / Q000276:immunology / Q000378:metabolism*; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005234:Fatty Liver / Q000188:drug therapy / Q000201:enzymology / Q000276:immunology; D006505:Hepatitis / Q000188:drug therapy / Q000201:enzymology / Q000276:immunology; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007948:Leukemia, Monocytic, Acute / Q000473:pathology; D008264:Macrophages / Q000166:cytology; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000166:cytology; D065626:Non-alcoholic Fatty Liver Disease; D000077333:Telmisartan
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D001562:Benzimidazoles; D001565:Benzoates; C111835:CCL2 protein, human; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D004791:Enzyme Inhibitors; D019881:Aminoacyltransferases; C059280:glutaminyl-peptide cyclotransferase; D000077333:Telmisartan
references.citation: J Biol Chem. 2011 Apr 22;286(16):14199-208
references.pmid: 21330373
references.citation: Hepatology. 2009 Jul;50(1):261-74
references.pmid: 19554540
references.citation: Curr Diab Rep. 2007 Jun;7(3):175-80
references.pmid: 17547834
references.citation: Mol Cell Biochem. 1981 Aug 11;38 Spec No(Pt 1):181-90
references.pmid: 6117006
references.citation: Gut. 2012 Mar;61(3):416-26
references.pmid: 21813474
references.citation: N Engl J Med. 2010 May 6;362(18):1675-85
references.pmid: 20427778
references.citation: J Exp Med. 2001 Jan 1;193(1):35-49
references.pmid: 11136819
references.citation: J Clin Gastroenterol. 2006 Mar;40 Suppl 1:S5-10
references.pmid: 16540768
references.citation: Oncologist. 2010;15 Suppl 4:14-22
references.pmid: 21115577
references.citation: Am J Physiol Gastrointest Liver Physiol. 2012 Jun 1;302(11):G1310-21
references.pmid: 22442158
references.citation: J Hepatol. 2006 Jun;44(6):1167-74
references.pmid: 16618517
references.citation: World J Gastroenterol. 2009 Feb 28;15(8):942-54
references.pmid: 19248193
references.citation: Eur J Immunol. 1995 Jan;25(1):64-8
references.pmid: 7531149
references.citation: Nat Med. 2005 Feb;11(2):183-90
references.pmid: 15685173
references.citation: Inflamm Allergy Drug Targets. 2011 Dec;10(6):509-36
references.pmid: 22150762
references.citation: Clin Sci (Lond). 2008 Sep;115(5):141-50
references.pmid: 18662168
references.citation: J Clin Invest. 1998 Dec 1;102(11):1933-41
references.pmid: 9835618
references.citation: Hepatology. 2005 Jun;41(6):1313-21
references.pmid: 15915461
references.citation: Int J Exp Pathol. 2006 Feb;87(1):1-16
references.pmid: 16436109
references.citation: Hepatology. 2004 Jul;40(1):46-54
references.pmid: 15239085
references.citation: QJM. 2010 Feb;103(2):71-83
references.pmid: 19914930
references.citation: Hepatology. 2010 Jul;52(1):79-104
references.pmid: 20578268
references.citation: Biochem J. 2006 Mar 15;394(Pt 3):635-45
references.pmid: 16248854
references.citation: EMBO Mol Med. 2011 Sep;3(9):545-58
references.pmid: 21774078
references.citation: J Exp Med. 1996 May 1;183(5):2379-84
references.pmid: 8642349
references.citation: J Biol Chem. 1957 May;226(1):497-509
references.pmid: 13428781
references.citation: Proc Natl Acad Sci U S A. 1987 Jun;84(11):3628-32
references.pmid: 3473473
references.citation: J Clin Invest. 2005 Feb;115(2):209-18
references.pmid: 15690074
references.citation: Liver Int. 2010 Jul;30(6):795-808
references.pmid: 20624207
references.citation: Science. 2001 Aug 31;293(5535):1673-7
references.pmid: 11533494
references.citation: World J Gastroenterol. 2012 Feb 28;18(8):727-35
references.pmid: 22371632
references.citation: Cancer Res. 2007 Oct 1;67(19):9417-24
references.pmid: 17909051
references.citation: Nature. 2011 Jun 08;475(7355):222-5
references.pmid: 21654748
references.citation: Dig Dis Sci. 2007 Dec;52(12):3455-64
references.pmid: 17410441
references.citation: J Clin Invest. 2006 Jun;116(6):1494-505
references.pmid: 16691291
references.citation: World J Gastroenterol. 2007 Sep 14;13(34):4539-50
references.pmid: 17729403
references.citation: Hepatology. 2012 Sep;56(3):912-21
references.pmid: 22505328