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Liver RBFOX2 regulates cholesterol homeostasis via Scarb1 alternative splicing in mice

ABSTRACT: RNA alternative splicing (AS) expands the regulatory potential of eukaryotic genomes. The mechanisms regulating liver-specific AS profiles and their contribution to liver function are poorly understood. Here, we identify a key role for the splicing factor RNA-binding Fox protein-2 (RBFOX2) in maintaining cholesterol homeostasis in an obesogenic environment in the liver. Using enhanced individual-nucleotide resolution UV-crosslinking and immunoprecipitation (eiCLIP), we identify physiologically relevant targets of RBFOX2 in mouse liver, including the scavenger receptor class B type I (Scarb1). RBFOX2 function is decreased in the liver in diet-induced obesity, causing a Scarb1 isoform switch and alteration of hepatocyte lipid homeostasis. Our findings demonstrate that specific AS programmes actively maintain liver physiology, and underlie the lipotoxic effects of obesogenic diets when dysregulated. Splice-switching oligonucleotides targeting this network alleviate obesityinduced inflammation in the liver and promote an anti-atherogenic lipoprotein profile in the blood, underscoring the potential of isoform-specific RNA therapeutics for treating metabolism-associated diseases.

INSTRUMENT(S): Orbitrap Fusion

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Liver

SUBMITTER: Miguel Prado

LAB HEAD: Miguel Prado

PROVIDER: PXD036976 | Pride | 2022-11-28

REPOSITORIES: Pride

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