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Abstract：
The nuclear receptor, farnesoid X receptor (FXR/NR1H4), is increasingly recognized as a promising drug target for metabolic diseases, including nonalcoholic steatohepatitis (NASH). Protein-coding genes regulated by FXR are well known, but whether FXR also acts through regulation of long non-coding RNAs (lncRNAs), which vastly outnumber protein-coding genes, remains unknown. Utilizing RNA-seq and global run-on sequencing (GRO-seq) analyses in mouse liver, we found that FXR activation affects the expression of many RNA transcripts from chromatin regions bearing enhancer features. Among these we discovered a previously unannotated liver-enriched enhancer-derived lncRNA (eRNA), termed FXR-induced non-coding RNA (Fincor). We show that Fincor is specifically induced by the hammerhead-type FXR agonists, including GW4064 and tropifexor. CRISPR/Cas9-mediated liver-specific knockdown of Fincor in dietary NASH mice reduced the beneficial effects of tropifexor, an FXR agonist currently in clinical trials for NASH and primary biliary cholangitis (PBC), indicating that amelioration of liver fibrosis and inflammation in NASH treatment by tropifexor is mediated in part by Fincor. Overall, our findings highlight that pharmacological activation of FXR by hammerhead-type agonists induces a novel eRNA, Fincor, contributing to the amelioration of NASH in mice. Fincor may represent a new drug target for addressing metabolic disorders, including NASH.
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.
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.
摘要：
核受体，法尼醇X受体（FXR/NR1H4），越来越被认为是代谢性疾病的有前途的药物靶标，包括非酒精性脂肪性肝炎（NASH）。FXR调控的蛋白质编码基因是众所周知的，但是FXR是否也通过调节长链非编码RNA（lncRNAs）起作用，大大超过蛋白质编码基因，仍然未知。利用小鼠肝脏中的RNA-seq和全局运行测序（GRO-seq）分析，我们发现FXR激活会影响携带增强子特征的染色质区域的许多RNA转录本的表达。在这些中，我们发现了以前未注释的富含肝脏的增强子来源的lncRNA（eRNA），称为FXR诱导的非编码RNA(Fincor)。我们证明Fincor是由锤头型FXR激动剂特异性诱导的，包括GW4064和热带。在饮食NASH小鼠中，CRISPR/Cas9介导的Fincor的肝脏特异性敲除降低了rotofexor的有益作用，目前正在进行NASH和原发性胆汁性胆管炎（PBC）临床试验的FXR激动剂，表明Tropifexor治疗NASH中肝纤维化和炎症的改善部分由Fincor介导。总的来说,我们的研究结果强调，通过锤头型激动剂对FXR的药理激活诱导了一种新的eRNA，Fincor,有助于改善小鼠NASH。Fincor可能代表解决代谢紊乱的新药物靶标，包括NASH。
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。
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。
