title: TFEB controls cellular lipid metabolism through a starvation-induced autoregulatory loop.
abstract: The lysosomal-autophagic pathway is activated by starvation and plays an important role in both cellular clearance and lipid catabolism. However, the transcriptional regulation of this pathway in response to metabolic cues is uncharacterized. Here we show that the transcription factor EB (TFEB), a master regulator of lysosomal biogenesis and autophagy, is induced by starvation through an autoregulatory feedback loop and exerts a global transcriptional control on lipid catabolism via Ppargc1α and Ppar1α. Thus, during starvation a transcriptional mechanism links the autophagic pathway to cellular energy metabolism. The conservation of this mechanism in Caenorhabditis elegans suggests a fundamental role for TFEB in the evolution of the adaptive response to food deprivation. Viral delivery of TFEB to the liver prevented weight gain and metabolic syndrome in both diet-induced and genetic mouse models of obesity, suggesting a new therapeutic strategy for disorders of lipid metabolism.
authors.affiliation: Telethon Institute of Genetics and Medicine (TIGEM), Naples, Italy. settembre@tigem.it
authors.forename: Carmine
authors.initials: C
authors.lastname: Settembre
authors.forename: Rossella
authors.initials: R
authors.lastname: De Cegli
authors.forename: Gelsomina
authors.initials: G
authors.lastname: Mansueto
authors.forename: Pradip K
authors.initials: PK
authors.lastname: Saha
authors.forename: Francesco
authors.initials: F
authors.lastname: Vetrini
authors.forename: Orane
authors.initials: O
authors.lastname: Visvikis
authors.forename: Tuong
authors.initials: T
authors.lastname: Huynh
authors.forename: Annamaria
authors.initials: A
authors.lastname: Carissimo
authors.forename: Donna
authors.initials: D
authors.lastname: Palmer
authors.forename: Tiemo Jürgen
authors.initials: TJ
authors.lastname: Klisch
authors.forename: Amanda C
authors.initials: AC
authors.lastname: Wollenberg
authors.forename: Diego
authors.initials: D
authors.lastname: Di Bernardo
authors.forename: Lawrence
authors.initials: L
authors.lastname: Chan
authors.forename: Javier E
authors.initials: JE
authors.lastname: Irazoqui
authors.forename: Andrea
authors.initials: A
authors.lastname: Ballabio
mesh_terms: D000818:Animals; D001343:Autophagy / Q000235:genetics; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000378:metabolism* / Q000494:pharmacology; D017173:Caenorhabditis elegans / Q000378:metabolism; D045744:Cell Line, Tumor; D004734:Energy Metabolism; D025461:Feedback, Physiological; D005786:Gene Expression Regulation; D006367:HeLa Cells; D006706:Homeostasis; D006801:Humans; D050356:Lipid Metabolism; D008099:Liver / Q000378:metabolism; D008247:Lysosomes / Q000235:genetics; D008297:Male; D024821:Metabolic Syndrome / Q000235:genetics / Q000378:metabolism* / Q000517:prevention & control; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009765:Obesity / Q000235:genetics / Q000378:metabolism*; D047493:PPAR alpha / Q000378:metabolism; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D013217:Starvation / Q000235:genetics / Q000378:metabolism*; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors; D014158:Transcription, Genetic; D015430:Weight Gain
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D047493:PPAR alpha; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; C484068:Tcfeb protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors