The protein RBFOX2 regulates cholesterol homeostasis – the maintenance of cholesterol levels – in the liver of mice with a fructose-rich diet. It does this by controlling alternative splicing of the gene ‘Scarb1’. The findings underscore the potential of using RNA-based drugs that target specific alternative splicing events to treat metabolism-associated diseases.

 

The Metabolism and Gene Regulation group at the London Institute of Medical Sciences, led by Professor Santiago Vernia have discovered that the protein RBFOX2 regulates cholesterol homeostasis in the liver of mice with a fructose-rich diet by controlling alternative splicing.

In our cells, genes are transcribed into mRNA that is then translated into proteins which carry out specific functions in the cell. A single gene can produce multiple different proteins. These different proteins are known as protein isoforms, as they are similar to each other but have different functions. Some protein isoforms are the result of alternative splicing, a process that ‘cuts’ freshly-transcribed mRNAs at different sections and then joins these sections together in different combinations. These different combinations each create different mRNA sequences, which are then translated into different proteins.

Alternative splicing is important in creating different protein isoforms with varied functions and properties. Dysregulation of alternative splicing is commonly linked to metabolism-associated diseases, which are diseases that can affect the body’s ability to produce energy needed for normal cell function. These diseases include metabolism-associated fatty liver disease (MAFLD), which can progress into severe liver failure and cancers. Therefore, understanding how alternative splicing contributes to these diseases is vital for the development of new treatments.

RNA Binding Fox-1 Homolog 2 (RBFOX2) is only found in specific tissues, and is known to regulate alternative splicing in many different biological processes such as differentiation of red blood cells, maturation of neurons, invasion of breast cancer, etc. However, its role in liver and metabolic regulation is less well characterised.

Using both human liver cells and mouse models, the team discovered RBFOX2 played a key role in regulating alternative splicing of a cluster of genes involved in maintaining lipid levels in the liver, such as the scavenger receptor class B type I (Scarb1) gene. In the presence of a lipid-rich diet, RBFOX2-deficiency leads to the accumulation of toxic lipids such as cholesterol in mouse liver, which is associated with an increased risk of MAFLD.

The group showed that RNA-based drugs modulating the alternative splicing of Scarb1 were able to revert the accumulation of toxic lipids in RBFOX2-deficient mouse hepatocytes, alleviate liver inflammation associated with diet-induced obesity in vivo, and promote a non-toxic lipid environment in the blood. These findings have demonstrated the potential of using RNA-based drugs that target specific alternative splicing events as a means to treat metabolism-associated diseases.

This paper by Helen AB Paterson and Sijia Yu was published in Nature Metabolism, as the 3rd paper in a series focusing on the role of RNA alternative splicing in metabolic regulation in health and disease.

READ FULL ARTICLE:Paterson, H.A.B., Yu, S., Artigas, N. et al. Liver RBFOX2 regulates cholesterol homeostasis via Scarb1 alternative splicing in mice. Nat Metab 4, 1812–1829 (2022). https://www.nature.com/articles/s42255-022-00681-yhttps://doi.org/10.1038/s42255-022-00681-y

Previous publications in the series include SRSF10 regulating RNA polyadenylation and a role for JNK splicing variants controlling RXRα phosphorylation and FGF21 expression. This research was funded by the MRC LMS.

This news article was written by Sijia Yu and Ester Seseri.