华中科技大学Ming Xiang团队近期取得重要工作进展，他们研究提出，恢复HMGCS2介导的酮体生成可缓解他克莫司诱导的肝脂代谢紊乱。相关研究成果2024年5月17日在线发表于《中国药理学报》杂志上。

据介绍，他克莫司是大环内酯类钙调神经磷酸酶抑制剂之一，是移植后最常用的免疫抑制剂。长期服用他克莫司会导致血脂异常并影响肝脏脂质代谢。

研究人员探讨了这种不良反应的作用模式和潜在机制。小鼠服用他克莫司（2.5 mg·kg⁻¹·d⁻¹，i.g.）持续10周，然后实施安乐死；采集血样和肝组织进行分析。研究人员发现，他克莫司给药在小鼠肝脏中诱导了显著的血脂异常和脂质沉积。在接受他克莫司治疗的心脏或肾脏移植患者中也观察到了血脂异常。他克莫司不会直接诱导脂肪酸的从头合成，但显著降低AML12细胞中的脂肪酸氧化（FAO）。

此外，研究人员发现他克莫司显著降低了生酮限速酶HMGCS2的表达，降低了正常肝细胞中负责脂质沉积的AML12细胞的生酮能力。

此外，研究人员发现他克莫司通过促进FKBP51-FoxO1复合物的形成，抑制了叉头盒蛋白O1（FoxO1）的核转位，从而降低了FoxO1与HMGCS2启动子的结合及其在AML12细胞中的转录能力。他克莫司诱导的HMGCS2缺失导致生酮减少和乙酰辅酶A积累增加，从而促进线粒体蛋白乙酰化，从而导致FAO功能抑制。通过尾静脉注射AAV8-TBG-HMGCS2，肝脏特异性HMGCS2过表达可逆转他克莫司诱导的线粒体蛋白乙酰化和FAO抑制，从而消除肝细胞中的脂质沉积。

总之，本研究证明了长期服用他克莫司诱导的肝脏脂质沉积和高脂血症的新机制，这是由于HMGCS2介导的生酮作用的丧失和随后的FAO抑制所致，为逆转他克莫斯诱导的不良反应提供了一个替代靶点。

附：英文原文

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

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

Issue&Volume: 2024-05-17

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 (2.5mg·kg1·d1, 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.

DOI: 10.1038/s41401-024-01300-0

Source: https://www.nature.com/articles/s41401-024-01300-0