Abstract
Peroxisome proliferator-activated receptor alpha (PPARα) activation-induced hepatomegaly is accompanied by hepatocyte hypertrophy around the central vein (CV) area and hepatocyte proliferation around the portal vein (PV) area. However, the molecular mechanisms underlying this spatial change of hepatocytes remains unclear. In this study, we examined the characteristics and possible reasons for the zonation distinction of hypertrophy and proliferation during PPARα activation-induced mouse liver enlargement. Mice were injected with corn oil or a typical mouse PPARα agonist WY-14643 (100 mg·kg−1·d−1, i.p.) for 1, 2, 3, 5 or 10 days. At each time point, the mice were sacrificed after the final dose, and liver tissues and serum were harvested for analysis. We showed that PPARα activation induced zonal changes in hepatocyte hypertrophy and proliferation in the mice. In order to determine the zonal expression of proteins related to hepatocyte hypertrophy and proliferation in PPARα-induced liver enlargement, we performed digitonin liver perfusion to separately destroy the hepatocytes around the CV or PV areas, and found that PPARα activation-induced increase magnitude of its downstream targets such as cytochrome P450 (CYP) 4 A and acyl-coenzyme A oxidase 1 (ACOX1) levels around the CV area were higher compared with those around the PV area. Upregulation of proliferation-related proteins such as cell nuclear antigen (PCNA) and cyclin A1 (CCNA1) after WY-14643-induced PPARα activation mainly occurred around the PV area. This study reveals that the zonal expression of PPARα targets and proliferation-related proteins is responsible for the spatial change of hepatocyte hypertrophy and proliferation after PPARα activation. These findings provide a new insight into the understanding of PPARα activation-induced liver enlargement and regeneration.
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Acknowledgements
This work was supported by the National Key R&D Program of China (2022YFA1104900), the National Natural Science Foundation of China (82025034, 82000593, 81973392, 82020108031), the Shenzhen Science and Technology Program (KQTD20190929174023858), the Local Innovative and Research Teams Project of Guangdong Pearl River Talents Program (2017BT01Y093), and the China Postdoctoral Science Foundation (2019TQ0398, 2020M673028).
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HCB, JY, and XY conceived and designed the project. JY performed the experiments. JY, YFZ, JNT, HLL, and CHC contributed to the animal models. YG, SCF, MH, and XY participated in the scientific discussion and research design. HCB, XY, and JY wrote and revised the manuscript.
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Yang, J., Yang, X., Zhang, Yf. et al. Peroxisome proliferator-activated receptor α agonist induces mouse hepatomegaly through the spatial hepatocyte enlargement and proliferation. Acta Pharmacol Sin 44, 2037–2047 (2023). https://doi.org/10.1038/s41401-023-01096-5
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DOI: https://doi.org/10.1038/s41401-023-01096-5
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