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Oleanolic acid promotes liver regeneration after partial hepatectomy via regulating pregnane X receptor signaling
Shaofei Song1, Hong Peng2, Yuan Li1
1Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China; Institute of Clinical Pharmacology, Sun Yat-sen University, Guangzhou, China.
Chemico-Biological Interactions
|March 21, 2024
Summary
Oleanolic acid (OA) significantly enhances liver regeneration after partial hepatectomy in mice. This compound promotes hepatocyte proliferation by activating the PXR signaling pathway, accelerating liver recovery.
Area of Science:
- Hepatology
- Pharmacology
- Molecular Biology
Background:
- Liver regeneration is critical after liver surgery or transplantation, but impaired regeneration occurs in some patients.
- Oleanolic acid (OA), a natural triterpenoid, shows protective effects in liver diseases, but its role in liver regeneration is unknown.
Purpose of the Study:
- To investigate the effect of Oleanolic acid (OA) on liver regeneration following partial hepatectomy (PHx).
- To elucidate the underlying molecular mechanisms, particularly the involvement of the PXR signaling pathway.
Main Methods:
- Mice underwent partial hepatectomy (PHx) and were treated with OA (50 mg/kg, twice daily).
- Hepatocyte proliferation was assessed by quantifying BrdU, Ki67, and PCNA positive cells.
- The role of PXR was investigated using molecular docking, luciferase reporter assays, and Pxr silencing experiments in vivo and in vitro (AML12 and HepRG cells).
Main Results:
- OA treatment significantly restored liver mass and increased the liver-to-body weight ratio post-PHx.
- OA promoted hepatocyte proliferation and increased the number of proliferating cell markers.
- OA activated the PXR signaling pathway, increasing nuclear PXR accumulation and downstream protein expression, while inhibiting cell cycle inhibitors (FOXO1, RBL2, CDKN1B) and promoting cell cycle activators (PCNA, CCND1, CCNE1).
- OA's effects on proliferation were dependent on PXR activation.
Conclusions:
- Oleanolic acid demonstrates a significant therapeutic potential in promoting liver regeneration after PHx.
- OA accelerates liver recovery by modulating the PXR signaling pathway, influencing hepatocyte proliferation and cell cycle regulation.
