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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Autophagy / genetics
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Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / metabolism*
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Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / pharmacology
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Caenorhabditis elegans / metabolism
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Cell Line, Tumor
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Energy Metabolism
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Feedback, Physiological
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Gene Expression Regulation
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HeLa Cells
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Homeostasis
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Humans
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Lipid Metabolism*
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Liver / metabolism
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Lysosomes / genetics
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Male
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Metabolic Syndrome / genetics
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Metabolic Syndrome / metabolism*
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Metabolic Syndrome / prevention & control
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Mice
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Mice, Inbred C57BL
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Mice, Transgenic
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Obesity / genetics
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Obesity / metabolism*
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PPAR alpha / metabolism
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Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
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Starvation / genetics
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Starvation / metabolism*
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Trans-Activators / metabolism
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Transcription Factors
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Transcription, Genetic
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Weight Gain
Substances
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Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
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PPAR alpha
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Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
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Ppargc1a protein, mouse
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Tcfeb protein, mouse
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Trans-Activators
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Transcription Factors