title: Fasting-induced hormonal regulation of lysosomal function.
abstract: 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.
authors.affiliation: MOE Key Laboratory of Bioinformatics, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China.
authors.forename: Liqun
authors.initials: L
authors.lastname: Chen
authors.affiliation: MOE Key Laboratory of Bioinformatics, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China.
authors.forename: Ke
authors.initials: K
authors.lastname: Wang
authors.affiliation: MOE Key Laboratory of Bioinformatics, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China.
authors.forename: Aijun
authors.initials: A
authors.lastname: Long
authors.affiliation: MOE Key Laboratory of Bioinformatics, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China.
authors.forename: Liangjie
authors.initials: L
authors.lastname: Jia
authors.affiliation: MOE Key Laboratory of Bioinformatics, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: MOE Key Laboratory of Bioinformatics, School of Life Sciences, Tsinghua University, Beijing 100084, China.
authors.forename: Haiteng
authors.initials: H
authors.lastname: Deng
authors.affiliation: Key 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.
authors.forename: Yu
authors.initials: Y
authors.lastname: Li
authors.affiliation: MOE Key Laboratory of Bioinformatics, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China.
authors.forename: Jinbo
authors.initials: J
authors.lastname: Han
authors.affiliation: MOE Key Laboratory of Bioinformatics, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China.
authors.forename: Yiguo
authors.initials: Y
authors.lastname: Wang
mesh_terms: D000818:Animals; D001343:Autophagy / Q000235:genetics / Q000502:physiology*; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics / Q000378:metabolism; D005215:Fasting / Q000502:physiology*; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism*; D051379:Mice; D008868:Microtubule Proteins / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D008868:Microtubule Proteins; D009687:Nuclear Proteins; C064972:TFEB protein, human; C484068:Tcfeb protein, mouse; D014157:Transcription Factors; C414620:fibroblast growth factor 21; D005346:Fibroblast Growth Factors; C109052:MID1 protein, human; D044767:Ubiquitin-Protein Ligases