Human Liver.Pain Disease

Avoiding death: Scientists refute long-standing beliefs about liver disease

WEHI researchers have shown for the first time that a crucial subset of liver cells cannot die, ruling out this type of cell death as a cause of common liver disease.

Surprising discovery redirects efforts to treat liver disease

Researchers at the Walter and Eliza Hall Institute (WEHI) have shown that common liver diseases are not caused by inflammatory cell death, as previously thought. This discovery ends a long-standing controversy in gastroenterology and points a new direction in treatment.

The study team looked at hepatitis B and non-alcoholic fatty liver disease, two liver diseases that affect billions of people worldwide, to find out what drives their progression.

Their surprising discovery – that liver cells are incapable of undergoing inflammatory cell death known as “necroptosis” – solves important unsolved questions in the field and will guide the development of new therapeutic interventions.

Tissues from liver diseases

A sample of liver tissue shows the typical features of liver disease, although a key gene required for necroptosis is missing. Fat-filled hepatocytes (yellow) and collagen build-up (red) are consistent with fibrosis and fatty liver disease. Photo credit: WEHI

At a glance

  • WEHI researchers have shown for the first time that an important type of liver cell cannot die, eliminating this type of cell death as a cause of common liver disease
    The surprising results define the role and relevance of necroptosis in non-cancerous liver diseases that affect billions of people worldwide
    The results will help inform new strategies for developing treatments for these liver diseases
  • The results published in the journal gastroenterologyprovide clarity on the much debated role of necroptosis in liver disease progression and provide fundamental insights to guide future preclinical and clinical studies.
  • The study was conducted in collaboration with researchers from the Peter Doherty Institute for Infection and Immunity and the University of Queensland by principal investigator Dr.

liver damage

Liver disease is a serious and increasing health burden worldwide. Over 30% of the world’s population suffer from non-alcoholic fatty liver disease, the most common liver disease, while 296 million people worldwide suffer from hepatitis B.

Simon Preston, Marcel Dörflinger, Marc Pellegrini

Study researchers (from left to right): Dr. Simon Preston, Dr. Marcel Doerflinger, Professor Marc Pellegrini. Photo credit: WEHI

Necroptosis has previously been considered by researchers to be essential for the development of these diseases. However, it remained unclear whether this type of cell death occurred in liver cells or in immune cells that had invaded the liver in response to infection or dietary damage.

“We tried to fill this research gap and define the role and relevance of necroptosis in common liver diseases,” said study leader Dr. villagers.

Researchers used several preclinical genetic models of liver disease, including nonalcoholic fatty liver disease and its advanced form, nonalcoholic steatohepatitis, and hepatitis B.

The team removed key genes required for necroptosis from liver cells known as “hepatocytes” to observe the impact on disease development.

They found that deleting these genes had little effect, with disease progression proving comparable to normal hepatocytes. This showed that necroptosis was not involved in the development of these liver pathologies.

“The liver is a vital organ because of its role in metabolism and detoxification of the body,” said Dr. villager.

“It is unclear why necroptosis is suppressed in liver tissue, but we speculate that this may be because the liver is constantly bathed in necroptotic signals such as gut microbial products, so limiting necroptosis could potentially protect the liver from excessive inflammation.”

Molecular Mechanisms

The research also uncovered the molecular mechanisms responsible for preventing liver cells from becoming necrotic.

After genetically profiling human liver tissue samples, the team discovered that hepatocytes are unable to produce a crucial protein essential for necroptosis, RIPK3.

Production of the RIPK3 protein has been restricted at the genetic level, where the RIPK3 gene has been blocked by a type of epigenetic modification known as “methylation”.

“Methylation acts as a genetic blockade, preventing the body’s protein production machinery from binding to the protein

DNS
DNA, or deoxyribonucleic acid, is a molecule made up of two long strands of nucleotides that wrap around each other, forming a double helix. It is the genetic material of humans and almost all other organisms, containing genetic instructions for development, function, growth and reproduction. Almost every cell in the human body has the same DNA. Most DNA is found in the nucleus (there it is called nuclear DNA), but a small amount of DNA can also be found in the mitochondria (there it is called mitochondrial DNA or mtDNA).

” data-gt-translate-attributes=”[{” attribute=””>DNA and building RIPK3 protein,” said Dr. Doerflinger.

“As a result, without this essential protein to carry out its necroptotic function, the cell death pathway can’t be initiated.”

Dr. Doerflinger said momentum had been growing in the development of inhibitors of RIPK3 for the potential treatment of liver diseases, but their potential clinical applicability had been limited by a lack of fundamental insights.

“These findings are a central piece of data that address many unanswered questions in the field that will guide future pre-clinical trials and clinical studies in this direction,” he said.

Reference: “Epigenetic Silencing of RIPK3 in Hepatocytes Prevents MLKL-mediated Necroptosis From Contributing to Liver Pathologies” by Simon P. Preston, Michael D. Stutz, Cody C. Allison, Ueli Nachbur, Quentin Gouil, Bang Manh Tran, Valerie Duvivier, Philip Arandjelovic, James P. Cooney, Liana Mackiewicz, Yanxiang Meng, Jan Schaefer, Stefanie M. Bader, Hongke Peng, Zina Valaydon, Pravin Rajasekaran, Charlie Jennison, Sash Lopaticki, Ann Farrell, Marno Ryan, Jess Howell, Catherine Croagh, Denuja Karunakaran, Carole Schuster-Klein, James M. Murphy, Theodora Fifis, Christopher Christophi, Elizabeth Vincan, Marnie E. Blewitt, Alexander Thompson, Justin A. Boddey, Marcel Doerflinger and Marc Pellegrini, 26 August 2022, Gastroenterology.
DOI: 10.1053/j.gastro.2022.08.040

The study was funded by the NHMRC and biotechnology start-up Anaxis Pharma Pty Ltd. It was performed in collaboration with Anaxis Pharma and Servier, a global pharmaceutical group.

Anaxis is a strategic joint venture established by WEHI and SYNthesis Research Pty Ltd, with a focus on necroptosis as a novel pathway of interest in human disease, developing first-in-class drug candidates for chronic inflammatory diseases including irritable bowel disease, Crohn’s disease, liver fibrosis, and reperfusion injury.


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