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Updated: Dec 26, 2025
Isolation of Regenerating Hepatocytes after Partial Hepatectomy in Mice
Published on: December 2, 2022
Lack of Multidrug Resistance-associated Protein 4 Prolongs Partial Hepatectomy-induced Hepatic Steatosis
Ajay C Donepudi1, Gregory J Smith1, Oladimeji Aladelokun1
1Department of Pharmaceutical Sciences.
Abstract:
Multidrug resistance-associated protein 4 (Mrp4) is an efflux transporter involved in the active transport of several endogenous and exogenous chemicals. Previously, we have shown that hepatic Mrp4 expression increases following acetaminophen overdose. In mice, these increases in Mrp4 expression are observed specifically in hepatocytes undergoing active proliferation. From this, we hypothesized that Mrp4 plays a key role in hepatocyte proliferation and that lack of Mrp4 impedes liver regeneration following liver injury and/or tissue loss. To evaluate the role of Mrp4 in these processes, we employed two-third partial hepatectomy (PH) as an experimental liver regeneration model. In this study, we performed PH-surgery on male wildtype (C57BL/6J) and Mrp4 knockout mice. Plasma and liver tissues were collected at 24, 48, and 72 h postsurgery and evaluated for liver injury and liver regeneration endpoints, and for PH-induced hepatic lipid accumulation. Our results show that lack of Mrp4 did not alter hepatocyte proliferation and liver injury following PH as evaluated by Ki-67 antigen staining and plasma alanine aminotransferase levels. To our surprise, Mrp4 knockout mice exhibited increased hepatic lipid content, in particular, di- and triglyceride levels. Gene expression analysis showed that lack of Mrp4 upregulated hepatic lipin1 and diacylglycerol O-acyltransferase 1 and 2 gene expression, which are involved in the synthesis of di- and triglycerides. Our observations indicate that lack of Mrp4 prolonged PH-induced hepatic steatosis in mice and suggest that Mrp4 may be a novel genetic factor in the development of hepatic steatosis.
Insights
Multidrug resistance-associated protein 4 (Mrp4) does not impact liver regeneration after partial hepatectomy. However, its absence leads to increased hepatic lipid accumulation and prolonged steatosis in mice.
Area of Science:
- Biochemistry
- Hepatology
- Molecular Biology
Background:
- Multidrug resistance-associated protein 4 (Mrp4) is an efflux transporter with known roles in chemical transport.
- Hepatic Mrp4 expression elevates after acetaminophen overdose, specifically in proliferating hepatocytes.
- This suggests a potential role for Mrp4 in hepatocyte proliferation and liver regeneration.
Purpose of the Study:
- To investigate the role of Mrp4 in hepatocyte proliferation and liver regeneration following partial hepatectomy (PH).
- To determine if Mrp4 deficiency impacts liver injury or regeneration after PH.
- To assess the effect of Mrp4 absence on PH-induced hepatic lipid accumulation.
Main Methods:
- Partial hepatectomy (PH) surgery was performed on wildtype and Mrp4 knockout mice.
- Liver injury and regeneration markers (Ki-67, ALT) were assessed at 24, 48, and 72 hours post-surgery.
- Hepatic lipid content and gene expression related to lipid metabolism were analyzed.
Main Results:
- Mrp4 knockout mice showed no significant differences in hepatocyte proliferation or liver injury compared to wildtype mice after PH.
- Unexpectedly, Mrp4 knockout mice exhibited significantly increased hepatic lipid content, particularly di- and triglycerides.
- Gene expression analysis revealed upregulation of lipin1 and diacylglycerol O-acyltransferase 1 and 2 in Mrp4 knockout livers.
Conclusions:
- Mrp4 is not essential for hepatocyte proliferation or liver regeneration following partial hepatectomy in mice.
- The absence of Mrp4 prolongs hepatic steatosis after PH, suggesting a role in lipid metabolism regulation.
- Mrp4 may represent a novel genetic factor involved in the development of hepatic steatosis.
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