Feedback repression of PPARα signaling by Let-7 microRNA

Peroxisome proliferator-activated receptor alpha (PPAR alpha) controls hepatic lipid homeostasis and is the target of lipid-lowering fibrate drugs. PPAR alpha activation represses expression of let-7 microRNA (miRNA), but the function of let-7 in PPAR alpha signaling and lipid metabolism is unknown. In the current study, a hepatocyte-specific let-7b/c2 knockout (let7b/c2(Delta Hep)) 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(Delta Hep) mice. RNA sequencing (RNA-seq) analysis reveals that hepatic PPAR alpha signaling is repressed in let7b/c2(Delta Hep) mice. Protein expression of the obligatePPAR alpha heterodimer partner retinoid X receptor alpha (RXR alpha) is reducedin the livers of let7b/c2(Delta Hep) mice. Ringfinger protein 8 (Rnf8), which is a direct target of let-7, is elevated in let7b/c2(Delta Hep) mouse liver and identified as a E3 ubiquitin ligase for RXR alpha. This study highlights a let-7-RNF8-RXR alpha regulatory axis that modulates hepatic lipid catabolism.

Automated summary

This study reveals the regulatory axis of let-7-RNF8-RXRα in modulating hepatic lipid catabolism.