Peroxisome proliferator-activated receptor a agonist induces mouse hepatomegaly through the spatial hepatocyte enlargement and proliferation

Peroxisome proliferator-activated receptor alpha (PPARa) 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 PPARa activation-induced mouse liver enlargement. Mice were injected with corn oil or a typical mouse PPARa 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 PPARa 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 PPARa-induced liver enlargement, we performed digitonin liver perfusion to separately destroy the hepatocytes around the CV or PV areas, and found that PPARa activation-induced increase magnitude of its downstream targets such as cytochrome P450 (CYP) 4 A and acylcoenzyme 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 PPARa activation mainly occurred around the PV area. This study reveals that the zonal expression of PPARa targets and proliferation-related proteins is responsible for the spatial change of hepatocyte hypertrophy and proliferation after PPARa activation. These findings provide a new insight into the understanding of PPARa activation-induced liver enlargement and regeneration.

Automated summary

In this study, it was found that activation of PPARa leads to hepatomegaly in mice, with hepatocyte hypertrophy around the central vein area and hepatocyte proliferation around the portal vein area. The study also revealed that the upregulation of PPARa targets is higher in the central vein area compared to the portal vein area, while the upregulation of proliferation-related proteins mainly occurs in the portal vein area. These findings provide new insights into the understanding of PPARa activation-induced liver enlargement and regeneration.