Dexamethasone-Induced Liver Enlargement Is Related to PXR/YAP Activation and Lipid Accumulation but Not Hepatocyte Proliferation
Dexamethasone-Induced Liver Enlargement Is Related to PXR/YAP Activation and Lipid Accumulation but Not Hepatocyte Proliferation
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DOI：
10.1124/dmd.120.000061
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发表时间：
2020-09-01
影响因子：
3.9
通讯作者：
Bi, Huichang
中科院分区：
文献类型：
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作者：
Jiao, Tingying;Yao, Xinpeng;Bi, Huichang
地塞米松（Dex）是一种广泛使用的抗炎药，据报道在临床实践和动物模型中可诱导肝脏肿大（肝肿大）。然而，其潜在机制尚未阐明。Dex是一种已知的甾烷X受体（PXR）激活剂。是相关蛋白（雅普）与化学诱导的肝肿大有关。在此，研究PXR和雅普通路在右旋糖酐诱导的肝肿大中的作用。PXR下游蛋白质，包括细胞色素P450（CYP）3A 11、2610和有机阴离子转运蛋白多肽2（OATP 2）（在小鼠中也称为SLCO 1A 4和SLC 21 A5）的上调表明，在高剂量Dex（50 mg/kg，i. p.）在双荧光素酶报告基因测定中，100 μ M的Dex激活PXR。Dex还增加了总雅普、核雅普和雅普下游蛋白的表达，包括结缔组织生长因子和富含半胱氨酸的血管生成诱导物61，表明雅普途径的激活。此外，PXR的激活促进了雅普的核转位。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，如叉头盒蛋白M1，c-MYC和表皮生长因子受体的表达显著降低。Dex对肝细胞增殖的抑制作用可能与其抑制炎症因子的抗炎作用有关。β-连环蛋白染色显示肝细胞增大，这主要归因于脂质如甘油三酯的积累。总之，高剂量Dex增加了肝脏大小，伴有肝细胞增大，这是由于PXR/雅普的激活及其对脂质蓄积的影响，而不是肝细胞增殖。这些发现为了解地塞米松诱导的肝肿大机制提供了新的见解。意义声明这项研究确定了孕烷X受体（PXR）和yes相关蛋白（雅普）途径在地塞米松（Dex）诱导的肝肿大中的作用。Dex诱导PXR/雅普活化，肝细胞增大，并促进肝脏增大伴脂质蓄积，如甘油三酯。然而，Dex的抗炎作用抑制了肝细胞增殖。这些发现为了解右旋糖酐诱导肝肿大的机制提供了新的见解。
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, 2610, and organic anion transporter polypeptide 2 (OATP2) (also known as SLCO1A4 and SLC21A5 in mouse), indicated PXR signaling was activated after high dose of Dex (50 mg/kg, i.p.), and Dex at 100 mu M 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. beta-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 STATEMENTThis 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.