Related Experiment Video

Updated: Jul 3, 2026

The Murine Choline-Deficient, Ethionine-Supplemented (CDE) Diet Model of Chronic Liver Injury
07:27

The Murine Choline-Deficient, Ethionine-Supplemented (CDE) Diet Model of Chronic Liver Injury

Published on: October 21, 2017

Death receptor 5 mediated-apoptosis contributes to cholestatic liver disease

Kazuyoshi Takeda1, Yuko Kojima, Kenichi Ikejima

  • 1Department of Immunology, Juntendo University School of Medicine, Hongo 2-1-1, Bunkyo-ku, Tokyo 113-8421, Japan. ktakeda@med.juntendo.ac.jp

Proceedings of the National Academy of Sciences of the United States of America
|August 1, 2008
PubMed

Insights

The TNF-related apoptosis-inducing ligand (TRAIL)/TRAIL receptor 2 (DR5) pathway drives cholestatic liver injury and biliary cirrhosis. Inhibiting this pathway may offer new treatments for primary sclerosing cholangitis.

Area of Science:

  • Hepatology
  • Immunology
  • Cell Biology

Background:

  • Chronic cholestasis leads to liver failure and fibrosis, but the underlying molecular mechanisms remain unclear.
  • The TNF-related apoptosis-inducing ligand (TRAIL) pathway is implicated in cell death, but its role in cholestatic liver injury is not fully understood.

Purpose of the Study:

  • To investigate the role of the TRAIL/TRAIL receptor 2 (DR5) pathway in the pathogenesis of cholestatic liver injury and biliary cirrhosis.
  • To determine if targeting DR5 could be a therapeutic strategy for cholestatic liver diseases.

Main Methods:

  • Utilized mouse models with targeted deficiencies in TRAIL or DR5.
  • Administered agonistic anti-DR5 monoclonal antibodies to induce cholangiocyte apoptosis and liver injury.
  • Examined DR5 expression and apoptosis in human cholangiocytes from patients with primary sclerosing cholangitis and primary biliary cirrhosis.

Main Results:

  • Mice lacking TRAIL or DR5 showed resistance to common bile duct ligation-induced cholestasis.
  • Anti-DR5 antibody treatment induced cholangitis and cholestatic liver injury in a strain-specific manner.
  • Human cholangiocytes expressed DR5, with elevated TRAIL and apoptosis in patients with primary sclerosing cholangitis and primary biliary cirrhosis.

Conclusions:

  • The TRAIL/DR5-mediated apoptosis pathway is a key regulator of cholestatic liver injury.
  • This pathway contributes significantly to the development of chronic cholestatic diseases, including primary sclerosing cholangitis.
  • Targeting DR5 presents a potential therapeutic avenue for managing these conditions.

More Related Videos

Bile Duct Ligation in Mice: Induction of Inflammatory Liver Injury and Fibrosis by Obstructive Cholestasis08:56

Bile Duct Ligation in Mice: Induction of Inflammatory Liver Injury and Fibrosis by Obstructive Cholestasis

Published on: February 10, 2015

Related Concept Videos

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...
Cirrhosis II: Pathophysiology01:24

Cirrhosis II: Pathophysiology

Cirrhosis is a progressive chronic liver injury caused by prolonged inflammation, excessive fibrotic remodeling, and impaired regeneration. Over time, repeated hepatic insults disrupt the liver’s architecture and function, leading to reduced blood flow, impaired bile drainage, and diminished metabolic capacity.Pathophysiology of cirrhosisCirrhosis arises from three main responses to chronic liver damage: inflammation, immune activation, and hepatocyte death. These processes lead to structural...
Apoptosis01:30

Apoptosis

Apoptosis is a combination of two Greek words, 'apo' and 'ptosis,' meaning separation and falling off, respectively. Hippocrates used this word to describe gangrene, which was caused due to bandaging of fractured bones. Apoptosis was distinguished from necrosis in 1970 when John Kerr reported observations of morphological changes occurring during apoptosis. During one experiment, he observed that the disruption of blood supply to the liver tissue resulted in a size reduction of the tissue.
The Intrinsic Apoptotic Pathway01:31

The Intrinsic Apoptotic Pathway

Internal cellular stress, such as cellular injury or hypoxia, triggers intrinsic apoptosis. The B-cell lymphoma 2 (Bcl-2) family of proteins are the primary regulators of the intrinsic apoptotic pathway. For example, during DNA damage, checkpoint proteins, such as Ataxia Telangiectasia Mutated (ATM protein) and Checkpoints Factor-2 (Chk2) proteins, are activated. These proteins phosphorylate p53 which further activates pro-apoptotic proteins, such as Bax, Bak, PUMA, and Noxa, and inhibits...
Cholesterol: Significance and Regulation01:29

Cholesterol: Significance and Regulation

Although not a source of energy, cholesterol plays a significant role as a foundational structure for bile salts, steroid hormones, and vitamin D, as well as being a crucial component of plasma membranes. Approximately 15% of blood cholesterol is derived from our diet, with the remainder synthesized from acetyl CoA by the liver and intestines. Cholesterol is eliminated from the body through its conversion into bile salts, which are eventually discarded in the feces.
Considering cholesterol and...
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 large...