Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China (T.J., X.P.Y., Yi.Z., Ya.Z., Y.G., S.F., P.C., X.L., Y.J., X.Y., M.H., H.B.) and Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland (F.J.G.).
Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China (T.J., X.P.Y., Yi.Z., Ya.Z., Y.G., S.F., P.C., X.L., Y.J., X.Y., M.H., H.B.) and Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland (F.J.G.)
Drug Metab Dispos. 2020 Sep;48(9):830-839. doi: 10.1124/dmd.120.000061. Epub 2020 Jun 19.
Dexamethasone (Dex), a widely prescribed anti-inflammatory drug, was reported to induce liver enlargement (hepatomegaly) in clinical practice and in animal models. However, the underlying mechanisms are not elucidated. Dex is a known activator of pregnane X receptor (PXR). Yes-associated protein (YAP) has been implicated in chemically induced liver enlargement. Here, the roles of PXR and YAP pathways were investigated in Dex-induced hepatomegaly. Upregulation of PXR downstream proteins, including cytochrome P450 (CYP) 3A11, 2B10, and organic anion transporter polypeptide 2 (OATP2), indicated PXR signaling was activated after high dose of Dex (50 mg/kg, i.p.), and Dex at 100 μM activated PXR in the dual-luciferase reporter gene assay. Dex also increased the expression of total YAP, nuclear YAP, and YAP downstream proteins, including connective tissue growth factor and cysteine-rich angiogenic inducer 61, indicating activation of the YAP pathway. Furthermore, nuclear translocation of YAP was promoted by activation of PXR. However, hepatocyte proliferation was inhibited with significant decrease in the expression of proliferation-related proteins cyclin D1 and proliferating cell nuclear antigen as well as other regulatory factors, such as forkhead box protein M1, c-MYC, and epidermal growth factor receptor. The inhibitory effect of Dex on hepatocyte proliferation was likely due to its anti-inflammation effect of suppression of inflammation factors. β-catenin staining revealed enlarged hepatocytes, which were mostly attributable to the accumulation of lipids, such as triglycerides. In summary, high-dose Dex increased liver size accompanied by enlarged hepatocytes, and this was due to the activation of PXR/YAP and their effects on lipid accumulation but not hepatocyte proliferation. These findings provide new insights for understanding the mechanism of Dex-induced hepatomegaly. SIGNIFICANCE STATEMENT: This study identified the roles of pregnane X receptor (PXR) and yes-associated protein (YAP) pathways in dexamethasone (Dex)-induced hepatomegaly. Dex induced PXR/YAP activation, enlarged hepatocytes, and promoted liver enlargement with lipid accumulation, such as triglycerides. However, hepatocyte proliferation was inhibited by the anti-inflammatory effect of Dex. These findings provide new insights for understanding the mechanism of Dex-induced hepatomegaly.
地塞米松（Dex）是一种广泛应用的抗炎药物，据报道在临床实践和动物模型中会导致肝脏增大（肝肿大）。然而，其潜在机制尚不清楚。地塞米松是已知的孕烷 X 受体（PXR）激活剂。Yes 相关蛋白（YAP）已被牵连到化学诱导的肝肿大中。在此，研究了 PXR 和 YAP 途径在 Dex 诱导的肝肿大中的作用。上调 PXR 下游蛋白，包括细胞色素 P450（CYP）3A11、2B10 和有机阴离子转运多肽 2（OATP2），表明高剂量 Dex（50mg/kg，腹腔注射）后 PXR 信号被激活，而 100μM Dex 在双荧光素酶报告基因检测中激活了 PXR。地塞米松还增加了总 YAP、核 YAP 和 YAP 下游蛋白的表达，包括结缔组织生长因子和富含半胱氨酸的血管生成诱导因子 61，表明 YAP 途径被激活。此外，PXR 的激活促进了 YAP 的核易位。然而，肝细胞增殖受到抑制，增殖相关蛋白 cyclin D1 和增殖细胞核抗原以及其他调节因子如叉头框蛋白 M1、c-MYC 和表皮生长因子受体的表达显著减少。Dex 对肝细胞增殖的抑制作用可能是由于其抑制炎症因子的抗炎作用。β-连环蛋白染色显示肝脏增大，这主要归因于甘油三酯等脂质的积累。总之，高剂量 Dex 增加了肝脏大小，伴随着肝细胞增大，这是由于 PXR/YAP 的激活及其对脂质积累的影响，而不是肝细胞增殖。这些发现为理解 Dex 诱导的肝肿大的机制提供了新的见解。
本研究确定了孕烷 X 受体（PXR）和 Yes 相关蛋白（YAP）途径在地塞米松（Dex）诱导的肝肿大中的作用。Dex 诱导 PXR/YAP 激活，增大肝细胞，促进肝脏增大伴脂质积累，如甘油三酯。然而，Dex 的抗炎作用抑制了肝细胞增殖。这些发现为理解 Dex 诱导的肝肿大的机制提供了新的见解。
