Splice-switching oligonucleotides (SSOs) modulating Scarb1 splicing revert the accumulation of lipotoxic species in RBFOX2-deficient mouse hepatocytes, alleviate liver inflammation associated with diet-induced obesity in vivo and promote an anti-atherogenic lipoprotein profile in the blood, demonstrating the potential of isoform-specific RNA therapeutics for metabolic pathologies. The gene discussed is SCARB1; the disease is obesity disorder.