Researchers have revealed that post-transcriptional RNA modifications protect against the development of non-alcoholic fatty liver disease. This mechanism may also underlie sex differences in liver fat content.
Fatty liver disease
Non-alcoholic fatty liver disease (NAFLD) develops from the accumulation of fats in the liver and can lead to advanced liver disease, such as cirrhosis. NAFLD is also associated with a heightened risk of cardiovascular disease. Like many complex diseases, interactions between genetic and environmental factors contribute to the onset of NAFLD.
In response to external stimuli, regulatory pathways in the liver alter gene expression to maintain metabolic homeostasis. Therefore, liver perturbations can lead to metabolic disturbances and even excessive build-up of fat. Many of these pathways affect mRNA biosynthesis. This includes post-transcriptional modification of RNAs, which are necessary for our response to environmental stressors.
Protective effects of RNA modification
A new study, published in Nature Metabolism, demonstrated that a specific RNA modification, known as N6-methyladenosine (m6A), can protect against fat accumulation in the liver. Methyltransferases, METTL14 and METTL3, work together as a complex to create this chemical modification on certain mRNA motifs. Previous work has shown that m6A impacts mRNA stability, which may result in corresponding changes in protein translation.
In this study, researchers at the University of California analysed RNA methylation patterns with m6A sequencing in mouse livers. Mice fed with a high-fat, high-carbohydrate Western diet exhibited lower m6A signatures and higher liver lipid content compared to mice fed on a high-fibre chow diet. Regardless of diet, m6A modifications were enriched in mRNAs involved in fatty acid biosynthesis (lipogenesis).
To assess the impact of m6A on liver fat content, the researchers also generated METTL14-knockout mice to inhibit m6A modifications. These mice exhibited increased levels of lipogenic proteins and liver fat accumulation, irrespective of diet. Altogether, these results support the role of the diet in the regulation of m6A modification. During dietary challenges, m6A modification leads to the repression of lipogenic proteins to protect against fat accumulation.
These findings were supported with an additional analysis of human livers. The team analysed a cohort of patients from the Mexican Obesity Surgery who had undergone liver biopsies during bariatric surgery. In humans, METTL14 expression, and thus m6A modification levels, correlated negatively with liver fat content and inflammation.
Sexual dimorphism in liver fat content
The researchers then explored whether m6A modifications exerted sex-specific effects on liver fat content. In line with previous studies, female mice consistently exhibited higher liver fat content than mice, irrespective of diet. Sex-specific differences in the impact of diet-regulated m6A modification may in part underlie this observation. The team found that m6A loss diminished the differences seen in lipogenic protein levels between male and female mice fed with chow diets. Strikingly, lack of m6A in male knockouts resulted in an increased liver fat content mirroring that of wild-type females.
Since m6A loss did not completely abolish differences in lipogenic proteins, there are likely additional factors governing the sexual dimorphism in liver fat content, such as other metabolic processes.
Altogether, these results point towards m6A-based gene therapy as a potential strategy for alleviating NAFLD. To test this hypothesis, the researchers generated a gene construct that promoted m6A modification in the liver. The administration of this gene construct into mouse models resulted in a reduced expression of genes involved in NAFLD progression.
Overall, this study has revealed that m6A markers influence lipid fat content, and thus affect NAFLD progression. It represents an attractive target to reduce NAFLD severity. As m6A modifications are implicated in diverse biological processes, further work may reveal its role in other diseases.
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