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.
authors.affiliation: Rosalind and Morris Goodman Cancer Research Centre, McGill University, 1160 Pine Avenue West, Montréal, QC H3A 1A3, Canada.
authors.forename: Cédric
authors.initials: C
authors.lastname: Chaveroux
authors.forename: Lillian J
authors.initials: LJ
authors.lastname: Eichner
authors.forename: Catherine R
authors.initials: CR
authors.lastname: Dufour
authors.forename: Aymen
authors.initials: A
authors.lastname: Shatnawi
authors.forename: Arkady
authors.initials: A
authors.lastname: Khoutorsky
authors.forename: Guillaume
authors.initials: G
authors.lastname: Bourque
authors.forename: Nahum
authors.initials: N
authors.lastname: Sonenberg
authors.forename: Vincent
authors.initials: V
authors.lastname: Giguère
mesh_terms: D000818:Animals; D047369:Chromatin Immunoprecipitation; D002952:Citric Acid Cycle / Q000502:physiology; D005234:Fatty Liver / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D053263:Gene Regulatory Networks; D006367:HeLa Cells; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D050356:Lipid Metabolism / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D065626:Non-alcoholic Fatty Liver Disease; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D060066:Protein Interaction Maps; D011960:Receptors, Estrogen / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000633:toxicity; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects; D025801:Ubiquitin / Q000378:metabolism; D000097983:ERRalpha Estrogen-Related Receptor
chemical_list: D046988:Proteasome Endopeptidase Complex; D011960:Receptors, Estrogen; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases; D025801:Ubiquitin; D000097983:ERRalpha Estrogen-Related Receptor