biostudies-literatureUnknownChen JNIDDK NIH HHSNLM NIH HHSNCI NIH HHSNIGMS NIH HHSThe 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 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 <i>FincoR</i>. We show that <i>FincoR</i> is specifically induced by the hammerhead-type FXR agonists, including GW4064 and tropifexor. CRISPR/Cas9-mediated liver-specific knockdown of <i>FincoR</i> 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 that amelioration of liver fibrosis and inflammation in NASH treatment by tropifexor is mediated in part by <i>FincoR</i>. Overall, our findings highlight that pharmacological activation of FXR by hammerhead-type agonists induces a novel eRNA, <i>FincoR</i>, contributing to the amelioration of NASH in mice. <i>FincoR</i> may represent a new drug target for addressing metabolic disorders, including NASH.bioRxiv : the preprint server for biology2023.11.20.567833https://www.ebi.ac.uk/biostudies/studies/S-EPMC10690184biostudies-literatureHammerhead-type FXR agonists induce an eRNA <i>FincoR</i> that ameliorates nonalcoholic steatohepatitis in mice.PMC10690184R01 DK095842R01 GM136922HHSN276201200017CR21 GM132778K22 CA204468R01 DK062777Li WChen JWang RKemper BKemper JKSun HXiong FfalseHammerhead-type FXR agonists induce an eRNA <i>FincoR</i> that ameliorates nonalcoholic steatohepatitis in mice.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 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 <i>FincoR</i>. We show that <i>FincoR</i> is specifically induced by the hammerhead-type FXR agonists, including GW4064 and tropifexor. CRISPR/Cas9-mediated liver-specific knockdown of <i>FincoR</i> 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 that amelioration of liver fibrosis and inflammation in NASH treatment by tropifexor is mediated in part by <i>FincoR</i>. Overall, our findings highlight that pharmacological activation of FXR by hammerhead-type agonists induces a novel eRNA, <i>FincoR</i>, contributing to the amelioration of NASH in mice. <i>FincoR</i> may represent a new drug target for addressing metabolic disorders, including NASH.2024-01-01T00:00:00Z2024 Feb2026-04-08T15:31:43.585Z2025-02-19T01:42:02.234ZS-EPMC106901843804522610.1101/2023.11.20.567833