Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006, China.
NMPA Key Laboratory for Research and Evaluation of Drug Metabolism & Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China.
Chem Biol Interact. 2022 Nov 1;367:110133. doi: 10.1016/j.cbi.2022.110133. Epub 2022 Aug 27.
Nuclear receptor pregnane X receptor (PXR) can induce significant liver enlargement through hepatocyte hypertrophy and proliferation. A previous report showed that during the process of PXR-induced liver enlargement, hepatocyte hypertrophy occurs around the central vein (CV) area while hepatocyte proliferation occurs around the portal vein (PV) area. However, the features of this spatial change remain unclear. Therefore, this study aims to explore the features of the spatial changes in hepatocytes in PXR-induced liver enlargement. PXR-induced spatial changes in hepatocyte hypertrophy and proliferation were confirmed in C57BL/6 mice. The liver was perfused with digitonin to destroy the hepatocytes around the CV or PV areas, and then the regional expression of proteins related to hepatocyte hypertrophy and proliferation was further measured. The results showed that the expression of PXR downstream proteins, such as cytochrome P450 (CYP) 3A11, CYP2B10, P-glycoprotein (P-gp) and organ anion transporting polypeptide 4 (OATP4) was upregulated around the CV area, while the expression of proliferation-related proteins such as cyclin B1 (CCNB1), cyclin D1 (CCND1) and serine/threonine NIMA-related kinase 2 (NEK2) was upregulated around the PV area. At the same time, the expression of cyclin-dependent kinase inhibitors such as retinoblastoma-like protein 2 (RBL2), cyclin-dependent kinase inhibitor 1B (CDKN1B) and CDKN1A was downregulated around the PV area. This study demonstrated that the spatial change in PXR-induced hepatocyte hypertrophy and proliferation is associated with the regional expression of PXR downstream targets and proliferation-related proteins and the regional distribution of triglycerides (TGs). These findings provide new insight into the understanding of PXR-induced hepatomegaly.
核受体孕烷 X 受体 (PXR) 可通过肝实质细胞肥大和增殖导致肝脏显著增大。先前的报告显示，在 PXR 诱导的肝脏增大过程中，肝实质细胞肥大发生在中央静脉 (CV) 区域周围，而肝实质细胞增殖发生在门静脉 (PV) 区域周围。然而，这种空间变化的特征尚不清楚。因此，本研究旨在探讨 PXR 诱导的肝肿大中肝实质细胞空间变化的特征。在 C57BL/6 小鼠中证实了 PXR 诱导的肝实质细胞肥大和增殖的空间变化。用去氧胆酸钠灌注肝脏以破坏 CV 或 PV 区域周围的肝实质细胞，然后进一步测量与肝实质细胞肥大和增殖相关的蛋白质的区域表达。结果表明，PXR 下游蛋白如细胞色素 P450 (CYP) 3A11、CYP2B10、P-糖蛋白 (P-gp) 和有机阴离子转运多肽 4 (OATP4) 的表达在 CV 区域上调，而增殖相关蛋白如细胞周期蛋白 B1 (CCNB1)、细胞周期蛋白 D1 (CCND1) 和丝氨酸/苏氨酸 NIMA 相关激酶 2 (NEK2) 的表达在 PV 区域上调。同时，PV 区域 cyclin 依赖性激酶抑制剂如视网膜母细胞瘤样蛋白 2 (RBL2)、细胞周期蛋白依赖性激酶抑制剂 1B (CDKN1B) 和 CDKN1A 的表达下调。本研究表明，PXR 诱导的肝实质细胞肥大和增殖的空间变化与 PXR 下游靶标和增殖相关蛋白的区域表达以及甘油三酯 (TGs) 的区域分布有关。这些发现为理解 PXR 诱导的肝肿大提供了新的视角。
