Feedback repression of PPARα signaling by Let-7 microRNA

Area of Science:

• Molecular biology
• Metabolic research
• Gene regulation

Background:

• Peroxisome proliferator-activated receptor α (PPARα) is crucial for liver lipid homeostasis and targeted by fibrate drugs.
• PPARα activation suppresses let-7 microRNA (miRNA) expression, but let-7's role in PPARα signaling and lipid metabolism remains unclear.

Purpose of the Study:

• To investigate the function of let-7 in PPARα signaling and hepatic lipid metabolism.
• To elucidate the regulatory mechanisms underlying let-7's control over lipid homeostasis.

Main Methods:

• Generated a hepatocyte-specific let-7b/c2 knockout (let7b/c2^ΔHep) mouse model.
• Utilized hepatocyte-specific let-7 sponge expression to inhibit let-7.
• Performed RNA sequencing (RNA-seq) to analyze gene expression changes.
• Assessed protein expression and ubiquitination of Retinoid X receptor α (RXRα).

Main Results:

• let7b/c2^ΔHep mice and let-7 inhibited mice showed resistance to diet-induced obesity and fatty liver.
• Hepatic PPARα signaling was repressed in let7b/c2^ΔHep mice.
• Ring finger protein 8 (Rnf8), a let-7 target, was elevated and acted as an E3 ubiquitin ligase for RXRα, reducing its protein levels.

Conclusions:

• Identified a novel let-7-RNF8-RXRα regulatory axis controlling hepatic lipid catabolism.
• Demonstrated that let-7 inhibition confers resistance to obesity and fatty liver.
• Highlighted a potential therapeutic strategy targeting the let-7-RNF8-RXRα pathway for metabolic disorders.