Selim Dahshan Hassan, Mokhlis Hamada Ahmed, Elsayed Abdelrahman M, Shatat Abdel-Aziz S, Salama Salama Abdou, Ismail Raed Shahat
Department of Pharmacology and Toxicology, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City, 11651, Cairo, Egypt.
Department of Pharmacy Practice, Faculty of Pharmacy, Sinai University-Kantara Branch, Ismailia City, 41636, Egypt.
Naunyn Schmiedebergs Arch Pharmacol. 2025 Jan 17. doi: 10.1007/s00210-025-03789-6.
The clinical use of dexamethasone (DXM) is associated with the development of non-alcoholic fatty liver disease (NAFLD). However, the mechanisms by which DXM-induced NAFLD is still incompletely known. Therefore, the current study aims to test the hypothesis that DXM-induced NAFLD is mediated by dysregulation of key genes involved in lipid metabolism and liraglutide (LG) can ameliorate these effects. The histopathological and biochemical analysis assessed the effects of DXM and/or LG in liver tissue. The computational analysis was performed to detect the glucocorticoid response elements (GRE) in the promotor regions of FASN and CD36 genes. The effects of DXM and LG on the expression of FASN and CD36 were determined by real-time quantitative reverse transcription PCR (RT-qPCR), western blot (WB) and immunohistochemical (IHC) analyses. The NAFLD induced by high-fat diet (HFD) and DXM was manifested by increased levels of liver enzymes, deterioration of histological architecture of the liver tissue and accumulation of fat droplets. Computational analysis revealed that the promotor regions of FASN and CD36 harper several GRE. Most importantly, treatment with DXM decreased phosphorylated adenosine monophosphate-activated protein kinase (p-AMPK) levels, while LG upregulate it. In addition, treatment with DXM increased expression of FASN and CD36, whereas LG ameliorated these effects in a dose-dependent manner. DXM-induced NAFLD is mediated by upregulation of FASN and CD36 expression which may be attributed to GRE. LG coupling with DXM mitigates this induction by downregulating FASN and CD36 levels and therefore mitigates the development of NAFLD.
地塞米松（DXM）的临床应用与非酒精性脂肪性肝病（NAFLD）的发生有关。然而，DXM诱发NAFLD的机制仍不完全清楚。因此，本研究旨在验证以下假设：DXM诱发的NAFLD是由脂质代谢相关关键基因的失调介导的，而利拉鲁肽（LG）可以改善这些影响。组织病理学和生化分析评估了DXM和/或LG对肝组织的影响。进行了计算分析以检测脂肪酸合酶（FASN）和CD36基因启动子区域中的糖皮质激素反应元件（GRE）。通过实时定量逆转录PCR（RT-qPCR）、蛋白质免疫印迹（WB）和免疫组织化学（IHC）分析确定DXM和LG对FASN和CD36表达的影响。高脂饮食（HFD）和DXM诱导的NAFLD表现为肝酶水平升高、肝组织结构恶化和脂肪滴积累。计算分析显示，FASN和CD36的启动子区域含有多个GRE。最重要的是，DXM治疗降低了磷酸化的腺苷单磷酸激活蛋白激酶（p-AMPK）水平，而LG上调了该水平。此外，DXM治疗增加了FASN和CD36的表达，而LG以剂量依赖的方式改善了这些影响。DXM诱导的NAFLD是由FASN和CD36表达上调介导的，这可能归因于GRE。LG与DXM联合使用可通过下调FASN和CD36水平减轻这种诱导作用，从而减轻NAFLD的发展。
