Related Experiment Video
Updated: May 22, 2026
Mechanism of Kemeng Fang's Inhibition of Podocyte Apoptosis in Rats with Membranous Nephropathy through the PI3K/AKT Signaling Pathway
Published on: August 23, 2024
Mitogen-activated protein kinase phosphatase (Mkp)-1 protects mice against acetaminophen-induced hepatic injury
Lyn M Wancket1, Xiaomei Meng, Lynette K Rogers
1Department of Veterinary Bioscience, The Ohio State University College of Veterinary Medicine, Columbus, Ohio, USA.
Abstract:
c-Jun N-terminal kinase (JNK) activation promotes hepatocyte death during acetaminophen overdose, a common cause of drug-induced liver failure. While mitogen-activated protein kinase (MAPK) phosphatase (Mkp)-1 is a critical negative regulator of JNK MAPK, little is known about the role of Mkp-1 during hepatotoxicity. In this study, we evaluated the role of Mkp-1 during acute acetaminophen toxicity. Mkp-1⁺/⁺ and Mkp-1⁻/⁻ mice were dosed ip with vehicle or acetaminophen at 300 mg/kg (for mechanistic studies) or 400 mg/kg (for survival studies). Tissues were collected 1-6 hr post 300 mg/kg dosing to assess glutathione levels, organ damage, and MAPK activation. Mkp-1⁻/⁻ mice exhibited more rapid plasma clearance of acetaminophen than did Mkp-1⁺/⁺ mice, indicated by a quicker decline of plasma acetaminophen level. Moreover, Mkp-1⁻/⁻ mice suffered more severe liver injury, indicated by higher plasma alanine transaminase activity and more extensive centrilobular apoptosis and necrosis. Hepatic JNK activity in Mkp-1⁻/⁻ mice was higher than in Mkp-1⁺/⁺ mice. Finally, Mkp-1⁻/⁻ mice displayed a lower overall survival rate and shorter median survival time after dosing with 400 mg/kg acetaminophen. The more severe phenotype exhibited by Mkp-1⁻/⁻ mice indicates that Mkp-1 plays a protective role during acute acetaminophen overdose, potentially through regulation of JNK.
Insights
Mitogen-activated protein kinase phosphatase-1 (Mkp-1) protects against acetaminophen overdose. Mice lacking Mkp-1 showed increased liver injury and JNK activation, highlighting Mkp-1's protective role in drug-induced liver failure.
Area of Science:
- Hepatology
- Toxicology
- Molecular Biology
Background:
- Acetaminophen overdose is a leading cause of drug-induced liver failure.
- c-Jun N-terminal kinase (JNK) activation contributes to hepatocyte death in acetaminophen toxicity.
- Mitogen-activated protein kinase (MAPK) phosphatase (Mkp)-1 is a key negative regulator of JNK, but its role in acetaminophen-induced liver injury is unclear.
Purpose of the Study:
- To investigate the role of Mkp-1 in acute acetaminophen toxicity.
- To determine if Mkp-1 influences JNK activation and liver injury severity following acetaminophen overdose.
Main Methods:
- Mice genetically deficient in Mkp-1 (Mkp-1⁻/⁻) and wild-type controls (Mkp-1⁺/⁺) were administered acetaminophen.
- Evaluated acetaminophen plasma clearance, liver injury markers (ALT activity, histology), hepatic JNK activation, and survival rates.
- Mechanistic studies used a 300 mg/kg dose, while survival studies used a 400 mg/kg dose.
Main Results:
- Mkp-1⁻/⁻ mice exhibited faster acetaminophen plasma clearance compared to Mkp-1⁺/⁺ mice.
- Mkp-1⁻/⁻ mice showed significantly more severe liver injury, characterized by higher ALT levels and increased centrilobular apoptosis and necrosis.
- Hepatic JNK activation was elevated in Mkp-1⁻/⁻ mice.
- Mkp-1⁻/⁻ mice had reduced survival rates and shorter median survival times after acetaminophen administration.
Conclusions:
- Mkp-1 plays a critical protective role in mitigating liver injury during acute acetaminophen overdose.
- The protective effect of Mkp-1 may be mediated through its negative regulation of JNK activation.
- Targeting Mkp-1 could be a potential therapeutic strategy for acetaminophen-induced liver failure.
Related Concept Videos
01:07MAPK Signaling Cascades
01:22PI3K/mTOR/AKT Signaling Pathway