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Hepatic Mrp4 induction following acetaminophen exposure is dependent on Kupffer cell function
Sarah N Campion1, Rachel Johnson, Lauren M Aleksunes
1Dept. of Pharmaceutical Sciences, Univ. of Connecticut, 69 North Eagleville Rd., Unit 3092, Storrs, CT 06269-3092, USA.
Summary
Kupffer cells protect the liver from acetaminophen (APAP) toxicity by regulating Mrp4 transporter expression. Depleting Kupffer cells exacerbates APAP liver injury and prevents Mrp4 induction.
Area of Science:
- Hepatology
- Immunology
- Toxicology
Background:
- Acetaminophen (APAP) overdose causes liver injury, associated with increased expression of multidrug resistance-associated proteins (Mrps).
- The regulatory mechanisms behind altered hepatic transporter expression during APAP hepatotoxicity are not fully understood.
- Kupffer cells, the resident liver macrophages, are implicated in inflammatory responses to APAP.
Purpose of the Study:
- To investigate the role of Kupffer cells in regulating hepatic transporter expression during APAP-induced liver injury.
- To determine if Kupffer cell-derived mediators influence the induction of Mrp4 transporter following APAP exposure.
Main Methods:
- C57BL/6J mice were depleted of Kupffer cells using clodronate liposomes.
- Mice were subsequently challenged with acetaminophen (APAP) to induce hepatotoxicity.
- Liver injury was assessed via plasma alanine aminotransferase levels; hepatic transporter protein expression (Mrp4) was analyzed using Western blot and immunohistochemistry.
Main Results:
- Kupffer cell depletion increased susceptibility to APAP hepatotoxicity.
- APAP treatment significantly upregulated Mrp4 transporter expression in control mice (10-33 fold at 48-72h).
- Kupffer cell depletion completely prevented the APAP-induced upregulation of Mrp4 and reduced elevated TNF-alpha and IL-1beta plasma levels.
Conclusions:
- Kupffer cells play a protective role in acetaminophen-induced liver injury.
- Mediators released by Kupffer cells in response to APAP are crucial for the induction of the Mrp4 transporter.
- Targeting Kupffer cell-mediated pathways may offer therapeutic strategies for APAP hepatotoxicity.
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