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

Settembre C, De Cegli R, Mansueto G, Saha PK, Vetrini F, Visvikis O, Huynh T, Carissimo A, Palmer D, Klisch TJ, Wollenberg AC, …, Ballabio A · 2013 · Nature Cell Biology · Atlas ID SET2013

What this study shows

The authors found that fasting switches on the TFEB gene in mouse liver, muscle and kidney, and that TFEB drives its own transcription by binding CLEAR sites in its promoter, an autoregulatory loop that starvation strengthens. Liver TFEB overexpression changed 773 genes up and 611 down, with lipid catabolism as the top category, and acted largely through PGC-1alpha and PPARalpha: 74% of TFEB-induced genes failed to rise in mice lacking PPARalpha. Mice lacking liver TFEB built up liver fat and mobilised fat poorly during fasting and gained more weight on a high-fat diet, while liver TFEB overexpression prevented and halted diet-induced obesity and improved glucose tolerance in obese ob/ob mice; the lipid effect required autophagy (lost in Atg7-deleted liver). In C. elegans, the TFEB homologue HLH-30 was needed for lipid mobilisation and survival during starvation. Boundary: Mice and worms, with TFEB delivered by virus at overexpression levels. mTORC1 was not manipulated or measured; its role is inferred from earlier work. Not tested in people.

Abstract

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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.

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At a glance

Evidence type	A Animal model Marked A because it is an animal intervention or observation study measuring an organismal outcome (model: Mice: 24 h fasting, liver-specific Tfeb knockout, liver-directed TFEB overexpression (helper-dependent adenovirus), high-fat diet and ob/ob obesity, liver Pgc1a and Atg7 deletion, Ppara knockout; HeLa cells, MEFs and primary hepatocytes; C. elegans hlh-30 mutants); the code names the system studied -- animal work can be rigorous and still not be human data.
Study type	4 - Animal Study
Model system	Mice: 24 h fasting, liver-specific Tfeb knockout, liver-directed TFEB overexpression (helper-dependent adenovirus), high-fat diet and ob/ob obesity, liver Pgc1a and Atg7 deletion, Ppara knockout; HeLa cells, MEFs and primary hepatocytes; C. elegans hlh-30 mutants
Journal	Nature Cell Biology
Year	2013
Peer reviewed	Yes
Record last updated	2026-10-01
Source	DOI 10.1038/ncb2718 · PMID 23604321 · Free full text (PMC3699877)

Extracted findings

These fields were extracted from the paper with AI assistance and have not been checked against the source. Read them as a pointer into the paper, not as curated claims; where they disagree with the curated summary above, the curated summary stands.

Intervention	Fasting; liver-specific Tfeb deletion; liver-directed TFEB overexpression (HDAd-TFEB); high-fat diet; ob/ob mice; hlh-30 mutant worms
Target	TFEB -> PGC-1alpha / PPARalpha lipid catabolism programme
Model	Mouse; C. elegans
Effect	TFEB raised lipid catabolism gene expression and fat breakdown; liver TFEB overexpression prevented diet-induced obesity, TFEB loss worsened it

In the Atlas

Cite this paper

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Settembre, C., De Cegli, R., Mansueto, G., Saha, P. K., Vetrini, F., Visvikis, O., Huynh, T., Carissimo, A., Palmer, D., Klisch, T. J., Wollenberg, A. C., Di Bernardo, D., Chan, L., Irazoqui, J. E., & Ballabio, A. (2013). TFEB controls cellular lipid metabolism through a starvation-induced autoregulatory loop. Nature Cell Biology. https://doi.org/10.1038/ncb2718

@article{SET2013,
  author       = {Settembre, C. and De Cegli, R. and Mansueto, G. and Saha, P. K. and Vetrini, F. and Visvikis, O. and Huynh, T. and Carissimo, A. and Palmer, D. and Klisch, T. J. and Wollenberg, A. C. and Di Bernardo, D. and Chan, L. and Irazoqui, J. E. and Ballabio, A.},
  title        = {{TFEB controls cellular lipid metabolism through a starvation-induced autoregulatory loop}},
  journal      = {Nature Cell Biology},
  year         = {2013},
  doi          = {10.1038/ncb2718},
  note         = {PMID: 23604321},
}

Cite this Atlas record

The record is the Atlas's own work — the evidence label, the extracted findings and the links. It is cited as part of the dataset, not as the paper.

Barton, O. (2026). Oliver's mTOR Atlas (record SET2013) [Data set]. https://mtor-atlas.org/study/SET2013/ · Dataset DOI 10.5281/zenodo.22059963

@misc{atlas_SET2013,
  author       = {Barton, Oliver},
  title        = {{Oliver's mTOR Atlas}, record SET2013},
  howpublished = {Data set},
  year         = {2026},
  url          = {https://mtor-atlas.org/study/SET2013/},
  doi          = {10.5281/zenodo.22059963}
}

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