Hammerhead-type FXR Agonists Induce FincoR eRNA for NASH Treatment in Mice

Core Concepts

Pharmacological activation of FXR by hammerhead-type agonists induces a novel liver-specific enhancer-derived lncRNA, FincoR, contributing to the amelioration of NASH in mice.

Abstract

The study explores how FXR activation affects the expression of long non-coding RNAs (lncRNAs) through the discovery of a liver-enriched enhancer-derived lncRNA named FincoR. The research demonstrates that FincoR is specifically induced by hammerhead-type FXR agonists and plays a crucial role in reducing liver fibrosis and inflammation in NASH treatment. The findings highlight the potential of FincoR as a new drug target for metabolic disorders, including NASH.

Stats

GW4064 treatment induced over 10-fold expression of FincoR in mouse liver.
190 high-confidence eRNAs were identified in mouse liver, with 14 upregulated and 5 downregulated by GW4064 treatment.
Short-time GW4064 treatment resulted in 590 up-regulated genes and 500 down-regulated genes.
ChIP assays confirmed increased recruitment of FXR, RXR𝛂, and BRD4 to the enhancer region close to the transcription start site of FincoR after GW4064 treatment.

Quotes

"FincoR is specifically induced by hammerhead-type FXR agonists, contributing to the amelioration of NASH."
"CRISPR/Cas9-mediated knockdown of FincoR reduced beneficial effects of tropifexor on liver fibrosis and inflammation."
"Tropifexor-mediated reduction in hepatic steatosis was independent of FincoR expression."

Key Insights Distilled From

Hammerhead-type FXR agonists induce an eRNA FincoR that ameliorates nonalcoholic steatohepatitis in mice

by Chen,J., Wan... at www.biorxiv.org 11-21-2023

https://www.biorxiv.org/content/10.1101/2023.11.20.567833v2

Deeper Inquiries

How might the induction of FincoR by hammerhead-type FXR agonists impact future drug development for metabolic disorders?

The induction of FincoR by hammerhead-type FXR agonists could have significant implications for future drug development in metabolic disorders. Since FincoR is specifically induced by these types of agonists, understanding its role and function could lead to the identification of novel therapeutic targets. By elucidating how FincoR contributes to reducing liver fibrosis and inflammation in NASH, researchers may uncover new pathways or mechanisms that can be targeted for developing more effective treatments for metabolic diseases like NASH.

What are potential implications if other nuclear receptors regulate or interact with FincoR?

If other nuclear receptors were found to regulate or interact with FincoR, it would broaden our understanding of the regulatory networks involved in metabolic processes. Interactions between different nuclear receptors and eRNAs like FincoR could reveal complex crosstalk mechanisms that coordinate gene expression patterns in response to various physiological cues. This knowledge could provide insights into how multiple signaling pathways converge on common downstream effectors, offering new opportunities for therapeutic interventions targeting these interactions.

How could studying the function and regulation of eRNAs like FincoR contribute to understanding broader biological processes beyond NASH?

Studying the function and regulation of eRNAs such as FincoR can contribute significantly to understanding broader biological processes beyond NASH. eRNAs play crucial roles in modulating gene expression programs across diverse cellular contexts, impacting various physiological functions beyond liver metabolism. Investigating how eRNAs are regulated by specific transcription factors like FXRs can shed light on general principles governing enhancer-mediated gene regulation. This knowledge can advance our comprehension of epigenetic mechanisms underlying complex diseases and normal cellular functions, providing a foundation for developing innovative therapies targeting dysregulated pathways implicated in a wide range of health conditions.