Liver RBFOX2 regulates cholesterol homeostasis via Scarb1 alternative splicing in mice

Nat Metab. 2022 Dec;4(12):1812-1829. doi: 10.1038/s42255-022-00681-y. Epub 2022 Dec 19.

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 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alternative Splicing* / genetics
  • Animals
  • Cholesterol / metabolism
  • Homeostasis
  • Liver / metabolism
  • Mice
  • Protein Isoforms / genetics
  • Protein Isoforms / metabolism
  • RNA / genetics
  • RNA Splicing Factors / genetics
  • RNA Splicing Factors / metabolism
  • RNA-Binding Proteins* / genetics
  • RNA-Binding Proteins* / metabolism
  • Scavenger Receptors, Class B / genetics
  • Scavenger Receptors, Class B / metabolism

Substances

  • RNA Splicing Factors
  • RNA-Binding Proteins
  • Protein Isoforms
  • RNA
  • Cholesterol
  • Scarb1 protein, mouse
  • Scavenger Receptors, Class B
  • Rbfox2 protein, mouse