| First Author | Chaveroux C | Year | 2013 |
| Journal | Cell Metab | Volume | 17 |
| Issue | 4 | Pages | 586-98 |
| PubMed ID | 23562079 | Mgi Jnum | J:198971 |
| Mgi Id | MGI:5499960 | Doi | 10.1016/j.cmet.2013.03.003 |
| Citation | Chaveroux C, et al. (2013) Molecular and genetic crosstalks between mTOR and ERRalpha are key determinants of rapamycin-induced nonalcoholic fatty liver. Cell Metab 17(4):586-98 |
| abstractText | mTOR and ERRalpha 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 ERRalpha that are involved in the TCA cycle and lipid biosynthesis. Genetic ablation of ERRalpha 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 ERRalpha activity exacerbates hepatic hyperlipidemia observed in rapamycin-treated mice. We further show that mTOR regulates ERRalpha 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/ERRalpha regulatory axis with significant clinical impact. |
