Upregulation of hepatic CD36 via glucocorticoid receptor activation contributes to dexamethasone-induced liver lipid metabolism disorder in mice

• Published in: Toxicology letters 2022-06, Vol.363, p.1-10
• Main Authors: Chen, Mingyang, Bai, Mengru, Yi, Yaodong, Lu, Shuanghui, Luo, Jun, Li, Ping, Zhang, Hengbin, Jiang, Huidi, Zhou, Hui
• Format: Article
• Language: English
• Subjects: Dexamethasone; Fatty acid transporter CD36; Glucocorticoid receptor; Glucocorticoids; Liver lipid metabolism disorder
• ISSN: 0378-4274; 1879-3169
• DOI: 10.1016/j.toxlet.2022.05.003

Glucocorticoids such as dexamethasone (DEX) are widely prescribed to treat numerous conditions and diseases. However, glucocorticoid-induced liver lipid metabolism disorder, even nonalcoholic fatty liver disease, has caused extensive attention. Since fatty acid transporters such as CD36 and FATP play crucial roles in hepatic fatty acid uptake, this work examined their potential involvement in DEX-induced liver lipid accumulation. Chronic DEX administration (1–5 mg/kg/day over 28 days) induced hepatic lipid accumulation in mice. Fatty acid uptake in HepG2 cells and mouse primary hepatocytes was also stimulated after incubation with 0.5–2 μM DEX. Meanwhile, qPCR and western blotting demonstrated dose-dependent upregulation of CD36 expression by DEX in the mouse liver and in cultured hepatocytes. Glucocorticoid receptor (GR) inhibition with mifepristone (RU486) and siRNA-mediated GR knockdown attenuated lipid accumulation in hepatocytes by inhibiting DEX-induced CD36 upregulation, and direct binding of GR to the CD36 promoter was demonstrated by luciferase reporter and chromatin immunoprecipitation assays. These results indicate that DEX promotes free fatty acid uptake leading to hepatic steatosis by upregulating CD36 expression via activation of GR. Thus, strategies aimed at inhibiting GR/CD36 expression or activity might help prevent or reduce the onset and progression of hepatic lipid metabolism disorders induced by glucocorticoid drugs. [Display omitted] •DEX promotes hepatic fatty acid uptake through upregulation of the fatty acid transporter CD36.•DEX upregulates hepatic CD36 expression by activating glucocorticoid receptor (GR).•GR blockade reduces hepatic steatosis by preventing DEX-induced CD36 upregulation.