Wnt/β-Catenin Signaling Drives Thioacetamide-Mediated Heteroprotection Against Acetaminophen-Induced Lethal Liver Injury

Abstract

Preplacement of compensatory tissue repair (CTR) by exposure to a nonlethal dose of a toxicant protects animals against a lethal dose of another toxicant. Although CTR is known to heteroprotect, the underlying molecular mechanisms are not completely known. Here, we investigated the mechanisms of heteroprotection using thioacetamide (TA): acetaminophen (APAP) heteroprotection model. Male Swiss Webster mice received a low dose of TA or distilled water (DW) vehicle 24 hours prior to a lethal dose of APAP. Liver injury, tissue repair, and promitogenic signaling were studied over a time course of 24 hours after APAP overdose to the TA- and DW-primed mice (TA + APAP and DW + APAP, respectively). Thioacetamide pretreatment afforded 100% protection against APAP overdose compared to 100% lethality in the DW + APAP-treated mice. Although hepatic Cyp2e1 was similar at the time of APAP administration, immediate activation of hepatic c-Jun N-terminal kinases (JNK) was observed in the TA + APAP-treated mice compared to its delayed activation in the DW + APAP group. In contrast to the DW + APAP group, the TA + APAP-treated mice exhibited extensive CTR, which was secondary to the timely activation of Wnt/β-catenin pathway. Our data indicate that rapid activation and appropriate termination of Wnt/β-catenin signaling and modulation of JNK activity underlie TA + APAP heteroprotection.

The Role of Stearoyl-coenzyme A Desaturase 1 in Liver Development, Function, and Pathogenesis

“…The expression and nuclear translocation of β-catenin significantly increase within minutes of hepatectomy and promote hepatocyte proliferation rate (20). In acetaminophen-induced liver injury, Wnt/β-catenin not only induces the expression of enzymes involved in drug metabolism such as cytochrome P450 2E1 and cytochrome P450 1A2 but also helps liver regeneration (21,22). In line with this finding, SCD1 gene expression was increased 3.5-fold in regenerating liver following major liver resection (23).…”

The roles of Wnt/β‐catenin pathway in tissue development and regenerative medicine

“…A recent study reported that Wnt/β-catenin signaling drives thioacetamidemediated heteroprotection against acetaminophen-induced lethal liver injury. They showed that that rapid activation and appropriate termination of Wnt/β-catenin signaling underlie in this heteroprotection (Dadhania, Bhushan, Apte, & Mehendale, 2017). The hair follicle is another most-investigated organ, which its morphogenesis and regeneration would be influenced intensely in the inhibition or disruption of the canonical Wnt/β-catenin signaling pathway (Andl, Reddy, Gaddapara, & Millar, 2002).…”

Effects of Newcastle disease vaccine on the liver and antioxidant enzymes of chicks

“…In various types of liver injury there are different degrees of oxidative stress that may impact directly liver specific enzymes, particularly glycogen synthase kinase (GSK) enzyme that regulate glycogen synthesis (25). Remarkably, oxidative stress can control hepatic cell proliferations and apoptosis, in part by regulating the activity of GSK (26)(27)(28), also by regulating several cell signalling pathways like β catenin/Wnt (29), p53 (30), NF-kB (nuclear factor kappa of activated B cells) (31), MAPK (mitogen-activated protein kinase) (32), and PI3K (phosphatidylinositide 3-kinase) (33). However, oxidative stress could be exacerbates hepatotoxicity by upstream the activity of GSK enzyme, and this fact may elucidate our result of high level of LGC in ND vaccinated groups at 7 and 15 days (see Table 2 and 3).…”