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

Acta Pharmacologica Sinica (2024)Cite this article

Abstract

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 reaction.

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Fig. 1: Tacrolimus induces dyslipidemia and lipid deposition in hepatocytes.
Fig. 2: Tacrolimus inhibits mitochondrial function and FAO in liver cells.
Fig. 3: Tacrolimus inhibits HMGCS2 expression and ketogenesis in hepatocytes.
Fig. 4: HMGCS2 protects hepatocyte from tacrolimus-induced lipid deposition via reducing mitochondrial protein acetylation and maintaining FAO.
Fig. 5: Specific HMGCS2 expression in the liver reverses tacrolimus-induced lipid deposition and hyperlipemia in mice.
Fig. 6: Tacrolimus inhibits HMGCS2 expression by reducing FoxO1 nuclear retention.
Fig. 7: Tacrolimus induces FKBP51-FoxO1 complex formation to preserve FoxO1 in cytoplasm.

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Acknowledgements

The research was supported by the National Natural Science Foundation of China (No. 82071749, 81703630). The experiments and data analysis were performed in part in the Medical Branch of the Analysis and Test Center of Huazhong University of Science and Technology.

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Author notes

  1. These authors contributed equally: Sen-lin Li, Hong Zhou

Authors and Affiliations

  1. Department of Pharmacology, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China

    Sen-lin Li, Jia Liu, Jian Yang, Hui-min Yuan, Meng-heng Wang, Ke-shan Yang & Ming Xiang

  2. Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China

    Hong Zhou

  3. Department of Biliary and Pancreatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China

    Li Jiang

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Contributions

SLL designed the study, conducted the experiments, analyzed data, and wrote the manuscript. HZ contributed to the design of the study, conducting experiments, and data collection. JL, JY, HMY, MHW, and KSY conducted the experiments. LJ offered technical support. MX supervised the whole project and revised the manuscript. All authors finally approved the version to be submitted.

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Correspondence to Ming Xiang.

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Li, Sl., Zhou, H., Liu, J. et al. Restoration of HMGCS2-mediated ketogenesis alleviates tacrolimus-induced hepatic lipid metabolism disorder. Acta Pharmacol Sin (2024). https://doi.org/10.1038/s41401-024-01300-0

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