m6A RNA modifications could explain why females have a higher liver fat content than males, with gene therapy being a potential treatment option for liver disease.
Non-alcoholic fatty liver can lead to advanced liver disease and is associated with a higher risk of cardiovascular disease. Fatty liver develops when liver fat content increases due to dietary or genetic factors, with females also tending to have a higher liver fat content than males. Understanding the mechanisms and risk factors behind higher liver fat content could be beneficial for disease prevention.
Scientists have previously identified a certain RNA modification called m6A – in which a methyl group attaches to an RNA chain – that alters protein production without affecting the DNA. In this study conducted in mice, researchers from the University of California, Los Angeles (CA, USA) discovered that m6A may protect against non-alcoholic fatty liver and also could explain why females tend to have a higher liver fat content than men.
The team used a unique mouse model without any m6A modifications in the liver alongside a control mouse model with m6A modifications. Their research involved comparing the effects of different levels of fat within an individuals’ diet on fat content in the liver of mice with and without RNA modifications.
The RNA theory suggests that there were no proteins present during the period of evolution of the first molecule of life on Earth. How then, could RNA serve as the evolutionary step before DNA and proteins?
Additionally, the team were able to correlate markers of m6A modifications with liver fat content using measurements gained from liver biopsies of human patients who had undergone bariatric surgery.
They discovered that in mice models without the m6A modification, differences in liver fat content between sexes were dramatically reduced, in comparison to those mouse models with the m6A modifications. This discovery suggests that the m6A modification could occur at different rates in those of different sexes.
Applying these findings in a preclinical model, the team used gene therapy to add modifications to key RNAs, which slowed or reduced the severity of liver disease. The team now hopes that this study will act as a springboard for future development of therapies that can protect against liver disease.