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On-line Access: 2023-06-13

Received: 2022-11-03

Revision Accepted: 2023-02-19

Crosschecked: 2023-07-21

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Citations:  Bibtex RefMan EndNote GB/T7714

 ORCID:

Xiao XU

https://orcid.org/0000-0002-2761-2811

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Journal of Zhejiang University SCIENCE B 2023 Vol.24 No.6 P.485-495

http://doi.org/10.1631/jzus.B2200562


Fibroblast growth factor 21 (FGF21) attenuates tacrolimus-induced hepatic lipid accumulation through transcription factor EB (TFEB)-regulated lipophagy


Author(s):  Zhensheng ZHANG, Li XU, Xun QIU, Xinyu YANG, Zhengxing LIAN, Xuyong WEI, Di LU, Xiao XU

Affiliation(s):  Zhejiang University School of Medicine, Hangzhou 310058, China; more

Corresponding email(s):   zjxu@zju.edu.cn

Key Words:  Autophagy, Fibroblast growth factor 21 (FGF21), Lipid, Lipophagy, Lysosome, Tacrolimus, Transcription factor EB (TFEB)


Zhensheng ZHANG, Li XU, Xun QIU, Xinyu YANG, Zhengxing LIAN, Xuyong WEI, Di LU, Xiao XU. Fibroblast growth factor 21 (FGF21) attenuates tacrolimus-induced hepatic lipid accumulation through transcription factor EB (TFEB)-regulated lipophagy[J]. Journal of Zhejiang University Science B, 2023, 24(6): 485-495.

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author="Zhensheng ZHANG, Li XU, Xun QIU, Xinyu YANG, Zhengxing LIAN, Xuyong WEI, Di LU, Xiao XU",
journal="Journal of Zhejiang University Science B",
volume="24",
number="6",
pages="485-495",
year="2023",
publisher="Zhejiang University Press & Springer",
doi="10.1631/jzus.B2200562"
}

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%T Fibroblast growth factor 21 (FGF21) attenuates tacrolimus-induced hepatic lipid accumulation through transcription factor EB (TFEB)-regulated lipophagy
%A Zhensheng ZHANG
%A Li XU
%A Xun QIU
%A Xinyu YANG
%A Zhengxing LIAN
%A Xuyong WEI
%A Di LU
%A Xiao XU
%J Journal of Zhejiang University SCIENCE B
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T1 - Fibroblast growth factor 21 (FGF21) attenuates tacrolimus-induced hepatic lipid accumulation through transcription factor EB (TFEB)-regulated lipophagy
A1 - Zhensheng ZHANG
A1 - Li XU
A1 - Xun QIU
A1 - Xinyu YANG
A1 - Zhengxing LIAN
A1 - Xuyong WEI
A1 - Di LU
A1 - Xiao XU
J0 - Journal of Zhejiang University Science B
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PB - Zhejiang University Press & Springer
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DOI - 10.1631/jzus.B2200562


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.

成纤维细胞生长因子21通过TFEB介导的脂噬缓解他克莫司引起的肝脏脂质积聚

张镇胜1,2,4,5,6, 徐力3,4,5,6, 邱洵1,2,4,5,6, 阳新宇1,2,4,5,6, 连正星1,2,4,5,6, 魏绪勇1,2,4,5,6, 鲁迪1,2,4,5,6, 徐骁1,2,4,5,6
1浙江大学医学院, 中国杭州市, 310058
2浙江省肿瘤融合与智能医学重点实验室,中国杭州市,310006
3浙江大学医学院附属第一医院肝胆胰外科, 中国杭州市, 310003
4浙江大学器官移植研究所, 中国杭州市, 310003
5卫健委多器官联合移植重点实验室, 中国杭州市, 310003
6西湖实验室(生命科学和生物医学浙江省实验室), 中国杭州市, 310024
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。
关键词: 自噬;成纤维细胞生长因子21(FGF21);脂质;脂噬;溶酶体;他克莫司(TAC);转录因子EB(TFEB)

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