title: M1 Muscarinic Receptor Deficiency Attenuates Azoxymethane-Induced Chronic Liver Injury in Mice.
abstract: Cholinergic nervous system regulates liver injury. However, the role of M1 muscarinic receptors (M1R) in modulating chronic liver injury is uncertain. To address this gap in knowledge we treated M1R-deficient and WT mice with azoxymethane (AOM) for six weeks and assessed liver injury responses 14 weeks after the last dose of AOM. Compared to AOM-treated WT mice, M1R-deficient mice had attenuated liver nodularity, fibrosis and ductular proliferation, α-SMA staining, and expression of α1 collagen, Tgfβ-R, Pdgf-R, Mmp-2, Timp-1 and Timp-2. In hepatocytes, these findings were associated with reductions of cleaved caspase-3 staining and Tnf-α expression. In response to AOM treatment, M1R-deficient mice mounted a vigorous anti-oxidant response by upregulating Gclc and Nqo1 expression, and attenuating peroxynitrite generation. M1R-deficient mouse livers had increased expression of Trail-R2, a promotor of stellate cell apoptosis; dual staining for TUNNEL and α-SMA revealed increased stellate cells apoptosis in livers from M1R-deficient mice compared to those from WT. Finally, pharmacological inhibition of M1R reduced H2O2-induced hepatocyte apoptosis in vitro. These results indicate that following liver injury, anti-oxidant response in M1R-deficient mice attenuates hepatocyte apoptosis and reduces stellate cell activation, thereby diminishing fibrosis. Therefore, targeting M1R expression and activation in chronic liver injury may provide therapeutic benefit.
authors.affiliation: Division of Gastroenterology and Hepatology, University of Maryland School of Medicine, Baltimore, Maryland, 21201.
authors.forename: Vikrant
authors.initials: V
authors.lastname: Rachakonda
authors.affiliation: Section of Gastroenterology and Hepatology, Georgia Regents University, Augusta, GA 30912.
authors.forename: Ravirajsinh N
authors.initials: RN
authors.lastname: Jadeja
authors.affiliation: Division of Gastroenterology and Hepatology, University of Maryland School of Medicine, Baltimore, Maryland, 21201.
authors.forename: Nathalie H
authors.initials: NH
authors.lastname: Urrunaga
authors.affiliation: Division of Gastroenterology and Hepatology, University of Maryland School of Medicine, Baltimore, Maryland, 21201.
authors.forename: Nirish
authors.initials: N
authors.lastname: Shah
authors.affiliation: Division of Gastroenterology and Hepatology, University of Maryland School of Medicine, Baltimore, Maryland, 21201.
authors.forename: Daniel
authors.initials: D
authors.lastname: Ahmad
authors.affiliation: Division of Gastroenterology and Hepatology, University of Maryland School of Medicine, Baltimore, Maryland, 21201.
authors.forename: Kunrong
authors.initials: K
authors.lastname: Cheng
authors.affiliation: Department of Pathology, University of Maryland School of Medicine, Baltimore, Maryland, 21201.
authors.forename: William S
authors.initials: WS
authors.lastname: Twaddell
authors.affiliation: Division of Gastroenterology and Hepatology, University of Maryland School of Medicine, Baltimore, Maryland, 21201.
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Raufman
authors.affiliation: Section of Gastroenterology and Hepatology, Georgia Regents University, Augusta, GA 30912.
authors.forename: Sandeep
authors.initials: S
authors.lastname: Khurana
mesh_terms: D000208:Acute Disease; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001397:Azoxymethane / Q000009:adverse effects*; D001652:Bile Ducts / Q000378:metabolism / Q000473:pathology; D002470:Cell Survival / Q000235:genetics; D004195:Disease Models, Animal; D005355:Fibrosis; D055166:Hepatic Stellate Cells / Q000187:drug effects / Q000378:metabolism; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology; D006965:Hyperplasia; D008107:Liver Diseases / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D020782:Matrix Metalloproteinases / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D018384:Oxidative Stress; D043643:Receptor, Muscarinic M1 / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D019714:Tissue Inhibitor of Metalloproteinases / Q000235:genetics / Q000378:metabolism
chemical_list: D043643:Receptor, Muscarinic M1; D019714:Tissue Inhibitor of Metalloproteinases; D020782:Matrix Metalloproteinases; D001397:Azoxymethane