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PMID: 23604321 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

TFEB controls cellular lipid metabolism through a starvation-induced autoregulatory loop.

Nature cell biology ·Vol. 15 ·No. 6 ·2013-06-00 ·Pages 647-58

Settembre C, De Cegli R, Mansueto G, Saha PK, Vetrini F, Visvikis O, Huynh T, Carissimo A, Palmer D, Klisch TJ, Wollenberg AC, Di Bernardo D, Chan L, Irazoqui JE, Ballabio A

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.

MeSH Terms
Animals Autophagy/genetics Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/metabolism,pharmacology Caenorhabditis elegans/metabolism Cell Line, Tumor Energy Metabolism Feedback, Physiological Gene Expression Regulation HeLa Cells Homeostasis Humans Lipid Metabolism Liver/metabolism Lysosomes/genetics Male Metabolic Syndrome/genetics,metabolism,prevention & control Mice Mice, Inbred C57BL Mice, Transgenic Obesity/genetics,metabolism PPAR alpha/metabolism Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha Starvation/genetics,metabolism Trans-Activators/metabolism Transcription Factors Transcription, Genetic Weight Gain
Chemicals
Basic Helix-Loop-Helix Leucine Zipper Transcription Factors PPAR alpha Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha Ppargc1a protein, mouse Tcfeb protein, mouse Trans-Activators Transcription Factors
Authors & Affiliations
15 authors, click to expand affiliations / ORCID
Settembre Carmine
Telethon Institute of Genetics and Medicine (TIGEM), Naples, Italy. [email protected]
De Cegli Rossella
Mansueto Gelsomina
Saha Pradip K
Vetrini Francesco
Visvikis Orane
Huynh Tuong
Carissimo Annamaria
Palmer Donna
Klisch Tiemo Jürgen
Wollenberg Amanda C
Di Bernardo Diego
Chan Lawrence
Irazoqui Javier E
Ballabio Andrea
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Article Info
Journal
Nature cell biology
Abbr.
Nat Cell Biol
ISSN
1476-4679
DOI
10.1038/ncb2718
Email
[email protected]
Published
2013-06-00
Epub
2013-00-21
Pages
647-58
Language
English
Region
England
NLM ID
100890575
PMCID
PMC3699877
Subset
IM
Grants
NINDS NIH HHS · R01 NS078072 · United States
NHLBI NIH HHS · R01 HL051586 · United States
NIDDK NIH HHS · P30 DK043351 · United States
NIDDK NIH HHS · P30-DK079638 · United States
NINDS NIH HHS · R01-NS078072 · United States
NIGMS NIH HHS · R01 GM101056 · United States
NHLBI NIH HHS · R01-HL51586 · United States
Telethon · TGM11CB6 · Italy
Telethon · TGM11SB1 · Italy
NIGMS NIH HHS · R01GM101056-01 · United States
NIDDK NIH HHS · P30 DK079638 · United States
Corrections
ErratumIn
-
CommentIn
PMID: 23728462
External Links
PubMed source DOI: 10.1038/ncb2718 PMC Full Text View journal details
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