title: Liver-Specific Deletion of Integrin-Linked Kinase in Mice Attenuates Hepatotoxicity and Improves Liver Regeneration After Acetaminophen Overdose.
abstract: Acetaminophen (APAP) overdose is the major cause of acute liver failure in the US. Prompt liver regeneration is critical for recovery after APAP hepatotoxicity, but mechanisms remain elusive. Extracellular matrix (ECM)-mediated signaling via integrin-linked kinase (ILK) regulates liver regeneration after surgical resection. However, the role of ECM signaling via ILK in APAP toxicity and compensatory regeneration is unknown, which was investigated in this study using liver-specific ILK knockout (KO) mice. ILK KO and wild-type (WT) mice were treated with 300 mg/kg APAP, and injury and regeneration were studied at 6 and 24 h after APAP treatment. ILK KO mice developed lower liver injury after APAP overdose, which was associated with decreased JNK activation (a key mediator of APAP toxicity). Further, higher glutathione levels after APAP treatment and lower APAP protein adducts levels, along with lower levels of CYP2E1, suggest decreased metabolic activation of APAP in ILK KO mice. Interestingly, despite lower injury, ILK KO mice had rapid and higher liver regeneration after APAP overdose accompanied with increased β-catenin signaling. In conclusion, liver-specific deletion of ILK improved regeneration, attenuated toxicity after APAP overdose, and decreased metabolic activation of APAP. Our study also indicates that ILK-mediated ECM signaling plays a role in the regulation of CYP2E1 and may affect toxicity of several centrilobular hepatotoxicants including APAP.
authors.affiliation: Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA.
authors.forename: Bharat
authors.initials: B
authors.lastname: Bhushan
authors.forename: Genea
authors.initials: G
authors.lastname: Edwards
authors.forename: Aishwarya
authors.initials: A
authors.lastname: Desai
authors.forename: George K
authors.initials: GK
authors.lastname: Michalopoulos
authors.forename: Udayan
authors.initials: U
authors.lastname: Apte
mesh_terms: D000082:Acetaminophen / Q000494:pharmacology*; D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism / Q000473:pathology; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism; D062787:Drug Overdose / Q000378:metabolism / Q000473:pathology; D005978:Glutathione / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D008115:Liver Regeneration / Q000187:drug effects*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D018345:Mice, Knockout; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D051176:beta Catenin / Q000378:metabolism; D000099200:Scaffold Protein ILK
chemical_list: D000082:Acetaminophen; D019392:Cytochrome P-450 CYP2E1; D005978:Glutathione; D017346:Protein Serine-Threonine Kinases; D051176:beta Catenin; D000099200:Scaffold Protein ILK