Restoration of HMGCS2-mediated ketogenesis alleviates tacrolimus-induced hepatic lipid metabolism disorder  

作　　者：Sen-lin Li Hong Zhou Jia Liu Jian Yang Li Jiang Hui-min Yuan Meng-heng Wang Ke-shan Yang Ming Xiang 

机构地区：[1]Department of Pharmacology,School of Pharmacy,Tongji Medical College,Huazhong University of Science and Technology,Wuhan,430030,China [2]Department of Pharmacy,Union Hospital,Tongji Medical College,Huazhong University of Science and Technology,Wuhan,430030,China [3]Department of Biliary and Pancreatic Surgery,Tongji Hospital,Tongji Medical College,Huazhong University of Science and Technology,Wuhan,430030,China

出　　处：《Acta Pharmacologica Sinica》2024年第9期1898-1911,共14页中国药理学报（英文版）

基　　金：National Natural Science Foundation of China(No.82071749,81703630)。

摘　　要：Tacrolimus,one of the macrolide calcineurin inhibitors,is the most frequently used immunosuppressant after transplantation.Long-term administration of tacrolimus leads to dyslipidemia and affects liver lipid metabolism.In this study,we investigated the mode of action and underlying mechanisms of this adverse reaction.Mice were administered tacrolimus(2.5 mg·kg^(−1)·d^(−1),i.g.)for 10 weeks,then euthanized;the blood samples and liver tissues were collected for analyses.We showed that tacrolimus administration induced significant dyslipidemia and lipid deposition in mouse liver.Dyslipidemia was also observed in heart or kidney transplantation patients treated with tacrolimus.We demonstrated that tacrolimus did not directly induce de novo synthesis of fatty acids,but markedly decreased fatty acid oxidation(FAO)in AML12 cells.Furthermore,we showed that tacrolimus dramatically decreased the expression of HMGCS2,the rate-limiting enzyme of ketogenesis,with decreased ketogenesis in AML12 cells,which was responsible for lipid deposition in normal hepatocytes.Moreover,we revealed that tacrolimus inhibited forkhead box protein O1(FoxO1)nuclear translocation by promoting FKBP51-FoxO1 complex formation,thus reducing FoxO1 binding to the HMGCS2 promoter and its transcription ability in AML12 cells.The loss of HMGCS2 induced by tacrolimus caused decreased ketogenesis and increased acetyl-CoA accumulation,which promoted mitochondrial protein acetylation,thereby resulting in FAO function inhibition.Liver-specific HMGCS2 overexpression via tail intravenous injection of AAV8-TBG-HMGCS2 construct reversed tacrolimus-induced mitochondrial protein acetylation and FAO inhibition,thus removing the lipid deposition in hepatocytes.Collectively,this study demonstrates a novel mechanism of liver lipid deposition and hyperlipidemia induced by long-term administration of tacrolimus,resulted from the loss of HMGCS2-mediated ketogenesis and subsequent FAO inhibition,providing an alternative target for reversing tacrolimus-induced adverse

关 键 词：fatty acid oxidation FKBP51-FoxO1 complex HMGCS2 KETOGENESIS mitochondrial protein acetylation TACROLIMUS 

分 类 号：R96[医药卫生—药理学]