| First Author | Yagai T | Year | 2021 |
| Journal | Cell Rep | Volume | 36 |
| Issue | 6 | Pages | 109506 |
| PubMed ID | 34380035 | Mgi Jnum | J:317340 |
| Mgi Id | MGI:6765703 | Doi | 10.1016/j.celrep.2021.109506 |
| Citation | Yagai T, et al. (2021) Feedback repression of PPARalpha signaling by Let-7 microRNA. Cell Rep 36(6):109506 |
| abstractText | Peroxisome proliferator-activated receptor alpha (PPARalpha) controls hepatic lipid homeostasis and is the target of lipid-lowering fibrate drugs. PPARalpha activation represses expression of let-7 microRNA (miRNA), but the function of let-7 in PPARalpha signaling and lipid metabolism is unknown. In the current study, a hepatocyte-specific let-7b/c2 knockout (let7b/c2(DeltaHep)) mouse line is generated, and these mice are found to exhibit pronounced resistance to diet-induced obesity and fatty liver. Let-7 inhibition by hepatocyte-specific let-7 sponge expression shows similar phenotypes as let7b/c2(DeltaHep) mice. RNA sequencing (RNA-seq) analysis reveals that hepatic PPARalpha signaling is repressed in let7b/c2(DeltaHep) mice. Protein expression of the obligate PPARalpha heterodimer partner retinoid X receptor alpha (RXRalpha) is reduced in the livers of let7b/c2(DeltaHep) mice. Ring finger protein 8 (Rnf8), which is a direct target of let-7, is elevated in let7b/c2(DeltaHep) mouse liver and identified as a E3 ubiquitin ligase for RXRalpha. This study highlights a let-7-RNF8-RXRalpha regulatory axis that modulates hepatic lipid catabolism. |
