TY - JOUR T1 - <strong>Dexamethasone-induced liver enlargement is related to PXR/YAP activation and lipid accumulation but not hepatocyte proliferation </strong> JF - Drug Metabolism and Disposition JO - Drug Metab Dispos DO - 10.1124/dmd.120.000061 SP - DMD-AR-2020-000061 AU - Tingying Jiao AU - Xinpeng Yao AU - Yingyuan Zhao AU - Yanying Zhou AU - Yue Gao AU - Shicheng Fan AU - Panpan Chen AU - Xuan Li AU - Yiming Jiang AU - Xiao Yang AU - Frank J. Gonzalez AU - Min Huang AU - Huichang Bi Y1 - 2020/01/01 UR - http://dmd.aspetjournals.org/content/early/2020/07/07/dmd.120.000061.abstract N2 - 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 CYP3A11, CYP2B10 and 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 CTGF and CYR61, 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 CCND1 and PCNA, as well as other regulatory factors, such as FOXM1, c-MYC and EGFR. The inhibitory effect of Dex on hepatocyte proliferation was likely due to its anti-inflammation effect of suppression of inflammation factors. CTNNB1 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, 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 PXR and YAP pathways in 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. ER -