Related Experiment Video

Updated: Sep 30, 2025

Reverse Yeast Two-hybrid System to Identify Mammalian Nuclear Receptor Residues that Interact with Ligands and/or Antagonists
10:51

Reverse Yeast Two-hybrid System to Identify Mammalian Nuclear Receptor Residues that Interact with Ligands and/or Antagonists

Published on: November 15, 2013

12.9K

Farnesoid X receptor (FXR) agonists induce hepatocellular apoptosis and impair hepatic functions via FXR/SHP pathway

Tianwei Zhang1,2, Shanshan Feng3, Jiahuan Li3

  • 1Shanghai Institute of Materia Medica, Chinese Academy of Science, Shanghai, 201203, China.

Archives of Toxicology
|March 10, 2022
PubMed

Insights

Farnesoid X receptor (FXR) agonists like OCA and Px-102 can harm liver cells by disrupting mitochondrial function and promoting apoptosis. Inhibiting FXR or SHP pathways may mitigate these toxic effects in hepatic diseases.

Area of Science:

  • Hepatology
  • Molecular Biology
  • Pharmacology

Background:

  • Farnesoid X receptor (FXR) is crucial for liver homeostasis and a therapeutic target for liver diseases.
  • Current FXR agonists face limitations due to potential adverse effects, necessitating a deeper understanding of their hepatotoxicity.

Purpose of the Study:

  • To elucidate the mechanism underlying FXR agonist-induced hepatotoxicity.
  • To compare the effects of two distinct FXR agonists, obeticholic acid (OCA) and Px-102, on liver cells.

Main Methods:

  • Assessed mitochondrial function (MMP, ROS, ATP) and cell apoptosis in hepatocytes treated with OCA and Px-102.
  • Utilized gene ablation or inhibition of FXR and SHP to evaluate their role in agonist-induced cytotoxicity.
  • Confirmed dose-related liver injury in a high-fat diet mouse model.

Main Results:

  • Both OCA and Px-102 impaired hepatocyte mitochondrial function and induced apoptosis.
  • FXR/SHP activation led to decreased PI3K/AKT phosphorylation and downregulation of hepatic genes.
  • OCA and Px-102 caused dose-dependent liver injury, decreased hepatocyte-specific genes, and disrupted liver regeneration and function in mice.

Conclusions:

  • FXR/SHP activation contributes to hepatotoxicity by affecting mitochondrial function, apoptosis, and key signaling pathways.
  • Developing intestinally biased FXR agonists or combining them with apoptosis inhibitors may offer safer therapeutic strategies for liver diseases.
Keywords:
ApoptosisFXR agonistFarnesoid X receptorHepatotoxicityObeticholic acidPx-102

More Related Videos

Cell Type-specific Gene Expression Profiling in the Mouse Liver10:06

Cell Type-specific Gene Expression Profiling in the Mouse Liver

Published on: September 17, 2019

7.8K
Author Spotlight: Establishing MASLD Cell Models for Investigating Disease Mechanisms and the Lipid-Lowering Effects of Koumiss07:03

Author Spotlight: Establishing MASLD Cell Models for Investigating Disease Mechanisms and the Lipid-Lowering Effects of Koumiss

Published on: July 19, 2024

1.1K

Related Concept Videos

Transducer Mechanism: Nuclear Receptors01:31

Transducer Mechanism: Nuclear Receptors

Nuclear receptors, or NRs, are unique transcription factors that regulate gene transcription and affect the cellular pathways involved in reproduction, development, or metabolism. Their ability to be stimulated by small lipophilic ligands and control vital cellular processes makes them ideal drug targets. Nearly 10-15% of currently prescribed drugs target these receptors.
About 48 different soluble family members of nuclear receptors are identified that can be divided into two main classes:
1.7K
NF-κB-dependent Signaling Pathway02:26

NF-κB-dependent Signaling Pathway

The transcription factor NF-κB was discovered in 1986 in the lab of Nobel laureate Professor David Baltimore, for its interaction with the immunoglobulin light chain enhancer in B-cells. After more than three decades of study, it is now evident that NF-κB regulates the expression of over 100 genes. Most of these genes play an essential role in the innate and adaptive immune responses as well as the inflammatory responses of animals.
NF-κB-dependent Signaling Mechanism
The...
7.9K
The Extrinsic Apoptotic Pathway01:17

The Extrinsic Apoptotic Pathway

The extrinsic apoptotic pathway is initiated when extracellular death-inducing signals, such as specific cytokines, activate the death receptors expressed on the cell surface. The immune cells involved in this pathway are natural killer cells (NK cells) and cytotoxic T-lymphocytes. NK cells are critical in innate immune response, while cytotoxic T-lymphocytes are associated with adaptive immune response. These cells recognize specific receptors expressed on the altered cells and activate...
6.7K
Hepatic Drug Excretion: Enterohepatic Cycling01:17

Hepatic Drug Excretion: Enterohepatic Cycling

Enterohepatic cycling involves the active secretion of drugs and their metabolites into the bile via transporters in the canalicular membrane of hepatocytes. This secretion is an integral part of the digestive process, releasing these substances into the gastrointestinal (GI) tract.
Post-release drugs and metabolites can be reabsorbed into the body from the intestine. For conjugated metabolites like glucuronides, reabsorption requires enzymatic hydrolysis by intestinal microflora. This...
1.9K
Liver Regeneration01:24

Liver Regeneration

The liver is an important organ in vertebrates that plays an essential role in metabolism. It is also responsible for storing and redistributing nutrients such as carbohydrates, fats, and vitamins in the body. Additionally, the liver releases bile salts which are critical for digesting food and eliminating toxic metabolites from the body.
Cells of Liver
The liver comprises four major types of cells— hepatocytes, stellate, Kupffer, and sinusoidal endothelial cells. The hepatocytes are...
3.4K
GPCRs Regulate Adenylyl Cylase Activity01:09

GPCRs Regulate Adenylyl Cylase Activity

Some GPCRs transmit signals through adenylyl cyclase (AC), a transmembrane enzyme. AC helps synthesize second messenger cyclic adenosine monophosphate (cAMP). AC catalyzes cyclization reaction and converts ATP to cAMP by releasing a pyrophosphate. The pyrophosphate is further hydrolyzed to phosphate by the enzyme pyrophosphatase, which drives cAMP synthesis to completion. However, cAMP is rapidly degraded to 5′ AMP by the enzymes phosphodiesterase (PDE), preventing overstimulation of...
6.0K