期刊
JOURNAL OF ZHEJIANG UNIVERSITY-SCIENCE B
卷 24, 期 6, 页码 485-495出版社
ZHEJIANG UNIV PRESS
DOI: 10.1631/jzus.B2200562
关键词
Autophagy; Fibroblast growth factor 21 (FGF21); Lipid; Lipophagy; Lysosome; Tacrolimus; Transcription factor EB (TFEB)
Tacrolimus (TAC) is an immunosuppressant commonly used after liver transplantation, but it is associated with post-transplant hyperlipemia. The mechanism behind this is unclear, and there is a need to explore preventive strategies for hyperlipemia. In a mouse model, we found that TAC treatment led to hyperlipemia and lipid accumulation in the liver. TAC also inhibited the autophagy-lysosome pathway and downregulated fibroblast growth factor 21 (FGF21). Overexpression of FGF21 reversed TAC-induced lipid accumulation and hyperlipemia by enhancing autophagy.
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 3 & beta; (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.
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