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.
非酒精性脂肪性肝炎,也被称为NASH,是一种严重的疾病,脂肪沉积在肝脏周围导致炎症,肿胀,对器官的疤痕和持久损害。尽管是全球肝脏相关死亡的主要原因之一,该疾病没有批准的治疗方法。被称为法尼酯X受体(或FXR)的蛋白质越来越被认为是非酒精性脂肪性肝炎的有希望的药物靶标。一旦激活,FXR有助于调节编码对肝脏健康重要的蛋白质的DNA区域的活性。然而,人们对FXR如何作用于非编码区知之甚少,不产生蛋白质但可以转录成具有重要生物学作用的RNA分子的DNA序列。作为回应,Chenetal.研究了非编码RNA的FXR激活是否与锤头FXR激动剂的临床益处有关,一种激活这种受体的合成化合物。要做到这一点,对小鼠肝脏进行遗传分析,以鉴定当FXR被激动剂激活时产生的非编码RNA.这些实验表明,激动剂激活的FXR诱导了一系列从DNA序列转录的非编码RNA,称为增强子。这有助于调节基因表达。特别是,锤头FXR激动剂导致肝脏特异性增强子RNA的产生,称为Fincor。使用rotofexor的其他实验,锤头FXR激动剂目前进入临床试验,表明,这种研究新药在低Fincor水平的非酒精性脂肪性肝炎小鼠模型中减少了益处。这表明这种增强子RNA可能在介导锤头FXR激动剂的临床益处中起关键作用,鼓励进一步研究其作用和治疗价值。