Abstract
Tacrolimus (TAC), also called FK506, is one of the classical immunosuppressants to prevent allograft rejection after liver transplantation. However, it has been proved to be associated with post-transplant hyperlipemia. The mechanism behind this is unknown, and it is urgent to explore preventive strategies for hyperlipemia after transplantation. Therefore, we established a hyperlipemia mouse model to investigate the mechanism, by injecting TAC intraperitoneally for eight weeks. After TAC treatment, the mice developed hyperlipemia (manifested as elevated triglyceride (TG) and low-density lipoprotein cholesterol (LDL-c), as well as decreased high-density lipoprotein cholesterol (HDL-c)). Accumulation of lipid droplets was observed in the liver. In addition to lipid accumulation, TAC induced inhibition of the autophagy-lysosome pathway (microtubule-associated protein 1 light chain 3β (LC3B) II/I and LC3B II/actin ratios, transcription factor EB (TFEB), protein 62 (P62), and lysosomal-associated membrane protein 1 (LAMP1)) and downregulation of fibroblast growth factor 21 (FGF21) in vivo. Overexpression of FGF21 may reverse TAC-induced TG accumulation. In this mouse model, the recombinant FGF21 protein ameliorated hepatic lipid accumulation and hyperlipemia through repair of the autophagy-lysosome pathway. We conclude that TAC downregulates FGF21 and thus exacerbates lipid accumulation by impairing the autophagy-lysosome pathway. Recombinant FGF21 protein treatment could therefore reverse TAC-caused lipid accumulation and hypertriglyceridemia by enhancing autophagy.
摘要
他克莫司(TAC), 也称为FK506, 是预防肝移植后同种异体移植排斥反应的经典免疫抑制剂之一. 然而, 它已被证明与移植后高脂血症有关. 但其背后的机制尚不清楚, 因此迫切需要探索移植后高脂血症的预防策略. 我们通过腹腔注射8周TAC建立了一个高脂血症小鼠模型来研究其机制. TAC处理后, 小鼠发生高脂血症(表现为甘油三酯(TG)和低密度脂蛋白胆固醇(LDL-c)升高, 以及高密度脂蛋白胆固醇(HDL-c)降低)以及肝脏脂质的累积. 除脂质积累外, TAC还抑制了自噬-溶酶体途径(LC3B II/I和LC3BII/actin比值、 转录因子EB(TFEB)、 P62和LAMP1), 并下调成纤维细胞生长因子21(FGF21)的表达. 而FGF21的过表达可逆转TAC诱导的TG积累. 在该小鼠模型中, 重组FGF21蛋白通过修复自噬-溶酶体途径改善肝脏脂质积累和高脂血症. 综上所述, TAC下调FGF21, 从而通过抑制自噬-溶酶体途径来加剧脂质积累. 此外, 重组FGF21蛋白处理可以通过增强自噬来逆转TAC引起的脂质积累和高甘油三酯血症.
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Acknowledgments
This work was supported by the National Key Research and Development Program of China (No. 2021YFA1100500), the National Natural Science Foundation of China (Nos. 92159202, 81930016, and 82102910), the Key Research & Development Plan of Zhejiang Province (No. 2019C03050), the Construction Fund of Key Medical Disciplines of Hangzhou (No. OO20200093), the Postdoctoral Science Foundation (No. 2020M671762), and the Medical and Health Technology Program in Zhejiang Province (No. WKJ-ZJ-2120), China.
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Zhensheng ZHANG, Li XU, Xun QIU, and Xiao XU designed the research. Zhensheng ZHANG, Li XU, Xun QIU, Xinyu YANG, and Zhengxing LIAN performed experiments. Zhensheng ZHANG, Li XU, and Xun QIU analyzed and interpreted data. Zhensheng ZHANG wrote the paper. Li XU, Xun QIU, Xuyong WEI, Di LU, and Xiao XU critically reviewed the manuscript. All authors have read and approved the final manuscript, and therefore, have full access to all the data in the study and take responsibility for the integrity and security of the data.
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Zhensheng ZHANG, Li XU, Xun QIU, Xinyu YANG, Zhengxing LIAN, Xuyong WEI, Di LU, and Xiao XU declare no competing interests.
All animal studies were approved by the Institutional Animal Care and Use Committee and the Ethics Committee of Zhejiang University (No. 1482).
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Zhang, Z., Xu, L., Qiu, X. et al. Fibroblast growth factor 21 (FGF21) attenuates tacrolimus-induced hepatic lipid accumulation through transcription factor EB (TFEB)-regulated lipophagy. J. Zhejiang Univ. Sci. B 24, 485–495 (2023). https://doi.org/10.1631/jzus.B2200562
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DOI: https://doi.org/10.1631/jzus.B2200562
Key words
- Autophagy
- Fibroblast growth factor 21 (FGF21)
- Lipid
- Lipophagy
- Lysosome
- Tacrolimus
- Transcription factor EB (TFEB)