Volume 27, No 6, Jun 2017
ISSN: 1001-0602
EISSN: 1748-7838 2018
impact factor 17.848*
(Clarivate Analytics, 2019)
Volume 27 Issue 6, June 2017: 748-763 | Open Access
ORIGINAL ARTICLES
Fasting-induced hormonal regulation of lysosomal function
Liqun Chen1,*, Ke Wang1,*, Aijun Long1, Liangjie Jia1, Yuanyuan Zhang1, Haiteng Deng2, Yu Li3, Jinbo Han1 and Yiguo Wang1
1MOE Key Laboratory of Bioinformatics, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China
2MOE Key Laboratory of Bioinformatics, School of Life Sciences, Tsinghua University, Beijing 100084, China
3Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China
Correspondence: Yiguo Wang, Tel: +86 10 62783209(wangyiguo@biomed.tsinghua.edu.cn)
Lysosomes are centers for nutrient sensing and recycling that allow mammals to adapt to starvation. Regulation of lysosome dynamics by internal nutrient signaling is well described, but the mechanisms by which external cues modulate lysosomal function are unclear. Here, we describe an essential role of the fasting-induced hormone fibroblast growth factor 21 (FGF21) in lysosome homeostasis in mice. Fgf21 deficiency impairs hepatic lysosomal function by blocking transcription factor EB (TFEB), a master regulator of lysosome biogenesis and autophagy. FGF21 induces mobilization of calcium from the endoplasmic reticulum, which activates the transcriptional repressor downstream regulatory element antagonist modulator (DREAM), and thereby inhibits expression of Mid1 (encoding the E3 ligase Midline-1). Protein phosphatase PP2A, a substrate of MID1, accumulates and dephosphorylates TFEB, thereby upregulating genes involved in lysosome biogenesis, autophagy and lipid metabolism. Thus, an FGF21-TFEB signaling axis links lysosome homeostasis with extracellular hormonal signaling to orchestrate lipid metabolism during fasting.
10.1038/cr.2017.45
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