Open AccessLiver-Specific Deletion of Integrin-Linked Kinase in Mice Attenuates Hepatotoxicity and Improves Liver Regeneration After Acetaminophen Overdose
Author(s) -
Bharat Bhushan,
Genea Edwards,
Aishwarya Desai,
George K. Michalopoulos,
Udayan Apte
Publication year - 2016
Publication title -
gene expression
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.591
H-Index - 46
eISSN - 1555-3884
pISSN - 1052-2166
DOI - 10.3727/105221616x691578
Subject(s) - acetaminophen , liver regeneration , liver injury , toxicity , integrin linked kinase , chemistry , pharmacology , cyp2e1 , regeneration (biology) , kinase , hepatocyte , microbiology and biotechnology , medicine , biochemistry , protein kinase a , biology , metabolism , cytochrome p450 , organic chemistry , in vitro , cyclin dependent kinase 2
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.