Non-alcoholic steatohepatitis can progress into fatal cirrhosis. Image credit: Servier Medical Art (CC BY 4.0)
Non-alcoholic steatohepatitis, also known as NASH, is a severe condition whereby fat deposits around the liver lead to inflammation, swelling, scarring and lasting damage to the organ. Despite being one of the leading causes of liver-related deaths worldwide, the disease has no approved treatment.
A protein known as Farnesoid X receptor (or FXR) is increasingly being recognized as a promising drug target for non-alcoholic steatohepatitis. Once activated, FXR helps to regulate the activity of DNA regions which are coding for proteins important for liver health. However, less is known about how FXR may act on non-coding regions, the DNA sequences that do not generate proteins but can be transcribed into RNA molecules with important biological roles.
In response, Chen et al. investigated whether FXR activation of non-coding RNAs could be linked to the clinical benefits of hammerhead FXR agonists, a type of synthetic compounds that activates this receptor.
To do so, genetic analyses of mouse livers were performed to identify non-coding RNAs generated when FXR was activated by the agonist. These experiments revealed that agonist-activated FXR induced a range of non-coding RNAs transcribed from DNA sequences known as enhancers, which help to regulate gene expression. In particular, hammerhead FXR agonists led to the production of a liver-specific enhancer RNA called Fincor.
Additional experiments using tropifexor, a hammerhead FXR agonist currently into clinical trials, showed that this investigational new drug had reduced benefits in a mouse model of non-alcoholic steatohepatitis with low Fincor levels. This suggested that this enhancer RNA may play a key role in mediating the clinical benefits of hammerhead FXR agonists, encouraging further research into its role and therapeutic value.
