Liver RBFOX2 regulates cholesterol homeostasis via Scarb1 alternative splicing in mice

Helen Paterson, Sijia Yu, Natalia Artigas, Miguel Prado, Nejc Haberman, Yi-Fang Wang, Andrew Jobbins, Elena Pahita, Joao Mokochinski, Zoe Hall, Maryse Guerin, Joao Paulo, Soon Seng Ng, Francesc Villarroya, Sheikh Tamir Rashid, Wilfried Le Goff, Boris Lenhard, Ines Cebola, Daniel Finley, Steven GygiChristopher R. Sibley, Santiago Vernia

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

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 a lipogenic environment in the liver. Using enhanced individual-nucleotide-resolution ultra-violet cross-linking and immunoprecipitation, 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 obesity-induced 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.

Original languageEnglish
Pages (from-to)1812-1829
Number of pages39
JournalNature Metabolism
Volume4
Issue number12
DOIs
Publication statusPublished - 19 Dec 2022

Keywords / Materials (for Non-textual outputs)

  • MAFLD
  • pre-mRNA alternative splicing
  • RBFOX2
  • cholesterol
  • triglyceride
  • Scarb1 (SR-BI/II)
  • splice-switching oligonucleotide (SSO)

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