CircFOXN2 alleviates glucocorticoid- and tacrolimus-induced dyslipidemia by reducing FASN mRNA stability by binding to PTBP1 during liver transplantation

Objective: We aimed to examine impacts and functional mechanism of circular RNA forkhead box N2 (FOXN2) in tacrolimus (TAC)- and dexamethasone (Dex)-induced lipid metabolism disorders. Methods: RNA level and protein contents in TAC, Dex or combined TAC plus Dex treated patients and Huh-7 cells were were measured utilizing quantitative real-time (qRT)-PCR and western blotting assays. Total cholesterol (TC) and triglyceride (TG) levels were determined using corresponding commercial kits and Oil red O staining. RNA immunoprecipitation and RNA pull-down verified the binding relationship among circFOXN2, polypyrimidine tract binding protein 1 (PTBP1) and fatty acid synthase (FASN). Male C57BL/6 mice were used to establish a dyslipidemia mouse model to validate the discoveries at the cellular level. Results: Dex treatment significantly promoted TAC-mediated the increase of TC and TG in serum samples and Huh-7 cells. Moreover, circFOXN2 was reduced but FASN was elevated in TAC-treated Huh-7 cells, and these expression trends were markedly enhanced by Dex co-treatment. Overexpression of circFOXN2 could reverse the accumulation of TC and TG and the upregulation of FASN and sterol regulatory element binding transcription factor 2 (SREBP2) mediated by Dex and TAC cotreatment. Mechanistically, circFOXN2 reduced FASN mRNA stability by recruiting PTBP1. The protective roles of circFOXN2 overexpression on lipid metabolism disorders were weakened by FASN overexpression. In vivo finding also disclosed that circFOXN2 greatly alleviated the dysregulation of lipid metabolism triggered by TAC plus Dex. Conclusion: CircFOXN2 alleviated the dysregulation of lipid metabolism induced by the combination of TAC and Dex by modulating the PTBP1/FASN axis.