Hammerhead-type FXR agonists induce an eRNA FincoR that ameliorates nonalcoholic steatohepatitis in mice
Year: 2024
Type: preprint
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 expression 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 induces many RNA transcripts from chromatin regions bearing enhancer features. Among these we discovered a previously unannotated liver-enriched enhancer-derived lncRNA (eRNA), termed FincoR. We further show that FincoR is specifically induced by 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 that amelioration of liver fibrosis and inflammation in NASH treatment by tropifexor is mediated in part by FincoR. Overall, our results indicate that pharmacological activation of FXR by hammerhead-type agonists induces a novel eRNA, FincoR, ameliorating NASH in mice. FincoR may represent a new drug target for combating metabolic disorders, including NASH.
Source: eLife
Authors: Jinjing Chen, Ruoyu Wang, Feng Xiong, Hao Sun, Byron Kemper, Wenbo Li, Jongsook Kim Kemper
Language: English
Subfield: Epidemiology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $2,500
Funders: American Diabetes Association, Welch Foundation, Cancer Prevention and Research Institute of Texas, John S. Dunn Foundation, National Institutes of Health, National Cancer Institute, National Institute of General Medical Sciences, National Institute of Diabetes and Digestive and Kidney Diseases
Awards: Regulation of Cholesterol Catabolism by Bile Acids, G134913906, G2321633756, G2464281560, Mechanisms Underlying Enhancer Rnp Mediated Gene Regulation And Genome Organization, G3816391948, G5462031285, Condensin-mediated enhancer and chromatin architectural control of breast cancer gene transcription, Coordination of gut-liver bile acid signaling by FXR, G9000222695, G9000254070, Recruitment of First-Time, Tenure-Track Faculty Members
OpenAlex ID: W4390971731