Molecular and genetic crosstalks between mTOR and ERRα are key determinants of rapamycin-induced nonalcoholic fatty liver

Cédric Chaveroux; Lillian J. Eichner; Catherine R. Dufour; Aymen Shatnawi; Arkady Khoutorsky; Guillaume Bourque; Nahum Sonenberg; Vincent Giguère

doi:10.1016/j.cmet.2013.03.003

Molecular and genetic crosstalks between mTOR and ERRα are key determinants of rapamycin-induced nonalcoholic fatty liver

Cédric Chaveroux, Lillian J. Eichner, Catherine R. Dufour, Aymen Shatnawi, Arkady Khoutorsky, Guillaume Bourque, Nahum Sonenberg, Vincent Giguère^*

^*Corresponding author for this work

Biochemistry and Molecular Genetics

Research output: Contribution to journal › Article › peer-review

130 Scopus citations

Abstract

mTOR and ERRα are key regulators of common metabolic processes, including lipid homeostasis. However, it is currently unknown whether these factors cooperate in the control of metabolism. ChIP-sequencing analyses of mouse liver reveal that mTOR occupies regulatory regions of genes on a genome-wide scale including enrichment at genes shared with ERRα that are involved in the TCA cycle and lipid biosynthesis. Genetic ablation of ERRα and rapamycin treatment, alone or in combination, alter the expression of these genes and induce the accumulation of TCA metabolites. As a consequence, both genetic and pharmacological inhibition of ERRα activity exacerbates hepatic hyperlipidemia observed in rapamycin-treated mice. We further show that mTOR regulates ERRα activity through ubiquitin-mediated degradation via transcriptional control of the ubiquitin-proteasome pathway. Our work expands the role of mTOR action in metabolism and highlights the existence of a potent mTOR/ERRα regulatory axis with significant clinical impact.

Original language	English (US)
Pages (from-to)	586-598
Number of pages	13
Journal	Cell Metabolism
Volume	17
Issue number	4
DOIs	https://doi.org/10.1016/j.cmet.2013.03.003
State	Published - Apr 2 2013

Funding

The authors are grateful to Dr. Fafournoux (INRA de Theix, France) for the gift of amino-acid-starved media. We thank Dr. Kwiatkowski (Harvard Medical School, Boston, MA) for the gift of TSC2 \u2212/\u2212 MEFs. We thank Dr. D. Avizonis for metabolomic analyses, C. Ouellet for mouse husbandry, M. Caron for bioinformatics analyses, T. Alain and M. Ghahremani for technical assistance, and D.W.K. Tsang, B.D. Fonseca, and G. Deblois for helpful discussions. This work was supported by grants from the Canadian Foundation for Innovation, the Canadian Institutes for Health Research (MOP-84227, MOP-111144), and a Program Project Grant from the Terry Fox Foundation (TFF-116128) to V.G. and N.S.

ASJC Scopus subject areas

Physiology
Molecular Biology
Cell Biology

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10.1016/j.cmet.2013.03.003

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title = "Molecular and genetic crosstalks between mTOR and ERRα are key determinants of rapamycin-induced nonalcoholic fatty liver",

abstract = "mTOR and ERRα are key regulators of common metabolic processes, including lipid homeostasis. However, it is currently unknown whether these factors cooperate in the control of metabolism. ChIP-sequencing analyses of mouse liver reveal that mTOR occupies regulatory regions of genes on a genome-wide scale including enrichment at genes shared with ERRα that are involved in the TCA cycle and lipid biosynthesis. Genetic ablation of ERRα and rapamycin treatment, alone or in combination, alter the expression of these genes and induce the accumulation of TCA metabolites. As a consequence, both genetic and pharmacological inhibition of ERRα activity exacerbates hepatic hyperlipidemia observed in rapamycin-treated mice. We further show that mTOR regulates ERRα activity through ubiquitin-mediated degradation via transcriptional control of the ubiquitin-proteasome pathway. Our work expands the role of mTOR action in metabolism and highlights the existence of a potent mTOR/ERRα regulatory axis with significant clinical impact.",

author = "C{\'e}dric Chaveroux and Eichner, {Lillian J.} and Dufour, {Catherine R.} and Aymen Shatnawi and Arkady Khoutorsky and Guillaume Bourque and Nahum Sonenberg and Vincent Gigu{\`e}re",

note = "Funding Information: The authors are grateful to Dr. Fafournoux (INRA de Theix, France) for the gift of amino-acid-starved media. We thank Dr. Kwiatkowski (Harvard Medical School, Boston, MA) for the gift of TSC2 −/− MEFs. We thank Dr. D. Avizonis for metabolomic analyses, C. Ouellet for mouse husbandry, M. Caron for bioinformatics analyses, T. Alain and M. Ghahremani for technical assistance, and D.W.K. Tsang, B.D. Fonseca, and G. Deblois for helpful discussions. This work was supported by grants from the Canadian Foundation for Innovation, the Canadian Institutes for Health Research (MOP-84227, MOP-111144), and a Program Project Grant from the Terry Fox Foundation (TFF-116128) to V.G. and N.S. ",

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T1 - Molecular and genetic crosstalks between mTOR and ERRα are key determinants of rapamycin-induced nonalcoholic fatty liver

AU - Chaveroux, Cédric

AU - Eichner, Lillian J.

AU - Dufour, Catherine R.

AU - Shatnawi, Aymen

AU - Khoutorsky, Arkady

AU - Bourque, Guillaume

AU - Sonenberg, Nahum

AU - Giguère, Vincent

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PY - 2013/4/2

Y1 - 2013/4/2

N2 - mTOR and ERRα are key regulators of common metabolic processes, including lipid homeostasis. However, it is currently unknown whether these factors cooperate in the control of metabolism. ChIP-sequencing analyses of mouse liver reveal that mTOR occupies regulatory regions of genes on a genome-wide scale including enrichment at genes shared with ERRα that are involved in the TCA cycle and lipid biosynthesis. Genetic ablation of ERRα and rapamycin treatment, alone or in combination, alter the expression of these genes and induce the accumulation of TCA metabolites. As a consequence, both genetic and pharmacological inhibition of ERRα activity exacerbates hepatic hyperlipidemia observed in rapamycin-treated mice. We further show that mTOR regulates ERRα activity through ubiquitin-mediated degradation via transcriptional control of the ubiquitin-proteasome pathway. Our work expands the role of mTOR action in metabolism and highlights the existence of a potent mTOR/ERRα regulatory axis with significant clinical impact.

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Molecular and genetic crosstalks between mTOR and ERRα are key determinants of rapamycin-induced nonalcoholic fatty liver

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