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, role of ECM-signaling via ILK in APAP-toxicity and compensatory regeneration is unknown, which was investigated in this study using liver-specific ILK-knock out (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 24hr 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 regulation of CYP2E1 and may affect toxicity of several centrilobular hepatotoxicants including APAP.

Liver Regeneration after Acetaminophen Hepatotoxicity

“…Wnt/b-catenin signaling is one of the few pathways that has been deeply investigated for its role in liver regeneration after APAP toxicity. 12,13,45,46 An incremental-dose study in mice showed activation of b-catenin signaling along with nuclear localization of b-catenin after a moderately toxic dose of APAP, in which compensatory liver regeneration was intact. 12 However, b-catenin signaling was inhibited after severe APAP overdose, in which regeneration was inhibited.…”

Energy metabolism couples hepatocyte integrin-linked kinase to liver glucoregulation and postabsorptive responses of mice in an age-dependent manner

“…The present study using the alb-cre system shows many of the same transient effects and shows that this transience extends to glucose homeostasis as well. Despite the transience of the unprovoked phenotype, mature hepILK-KO mice possess accelerated recovery from chemical injury (6), regeneration (3), and improved insulin resistance resulting from overnutrition (64), regardless of which of the two cre systems are used. Thus, although the effects of gene deletion may become masked to conditions for which they have adapted, provocative stimuli for which they have not adapted expose the role of the deleted gene.…”

“…This was hypothesized to be a result of compensatory proliferation due to loss of contact inhibition. Even after morphological phenotypes are resolved, exposure of these mice to hepatic resection or toxicity results in an enhanced regenerative response (3,6,12,13,18).…”

Effect of Liposomal Curcumin on Acetaminophen Hepatotoxicity by Down-regulation of Oxidative Stress and Matrix Metalloproteinases

“…The hepatoprotective effect of LCC could be linked to its already proven inhibitory effect on iNOS activity (52) and MDA production (51) as well as its ability to maintain the thiol pool (53) and to improve catalase production (54). In addition to mitochondrial oxidative stress, many other cellular processes, including inflammation, microcirculatory dysfunction and extracellular matrix degradation, have been shown to be involved in the pathogenesis of APAP-induced liver injury (46,55).…”