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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 language | English |
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Pages (from-to) | 1812-1829 |
Number of pages | 39 |
Journal | Nature Metabolism |
Volume | 4 |
Issue number | 12 |
DOIs | |
Publication status | Published - 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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Dive into the research topics of 'Liver RBFOX2 regulates cholesterol homeostasis via Scarb1 alternative splicing in mice'. Together they form a unique fingerprint.Projects
- 1 Finished
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Elucidating RNA metabolism changes underlying the progressive neural cell biology of ALS
9/05/19 → 30/04/24
Project: Research