Alcohol-related liver disease: New drug targets found
03 June, 2020
A report combining analysis of patient samples with mice studies has discovered new drug targets for alcohol-related liver disease, which, currently, doctors can only just treat by transplant.
Alcohol-related liver disease (ALD), as its name suggests, is harm to the liver that the excessive consumption of alcohol causes.
As time passes, excessive alcohol consumption can cause inflammation and scarring (fibrosis) of liver tissue, and could eventually bring about liver failure.
According to an analysis of trends published on the globe Journal of Hepatology in 2017, 16.5% of most liver transplants between 2002-2015 occurred consequently of ALD, making the condition the 3rd most common reason behind transplantation.
ALD is irreversible, and there happens to be no treatment aside from liver transplant.
Doctors typically advise persons to stop drinking alcohol altogether to avoid further damage. This has limited success rates in people that have alcohol misuse disorder and even has risks alone.
A team from Massachusetts General Hospital have already been attempting to identify desperately needed treatments for ALD.
In a fresh study featured in the journal PNAS, they describe the molecular basis for the condition and possible new drug targets.
Analyzing liver cells
To better know very well what causes the liver damage observed in ALD, the researchers started by analyzing human liver samples taken from a cohort of 51 people with varying degrees of ALD severity.
They looked at the expression of different genes in the samples using a technology called RNA sequencing.
They found that the expression of several genes, including one called cGAS, was higher in people with more severe disease.
The gene cGAS is part of a known biological pathway which involves the molecule IRF3. Researchers know that activation of the pathway causes the death of liver cells.
In persons with ALD, the cGAS-IRF3 pathway initiates an inflammatory response that damages nearby cells and will eventually cause the liver to fail.
This study confirms the importance of cGASin ALD-related liver damage and implies that the amount of cGAS expression in liver tissue has links with the severity of the disease.
Uncovering the mechanism
Scientists understand that the cGAS-IRF3 pathway is important in ALD but have already been unsure about how precisely alcohol activates the IRF3 molecule, and what causes inflammation to spread through the entire liver.
Understanding this process is crucial for the reason that propagation of the inflammatory signal can continue to damage the liver, even though the person has stopped drinking alcohol.
To research this in greater detail, the researchers considered animal models. They fed mice the Lieber-DeCarli diet, which is an established model of chronic alcohol abuse in rodents. They discovered that the mice had increased degrees of both cGAS and IRF3 in their liver tissue.
If excess alcohol causes a rise in the expression of the molecules, can removing them drive back alcohol-induced damage?
To test this, the team genetically engineered mice to remove the cGAS protein. When subjected to alcohol, these mice had both less IRF3 activation and less harm to their liver.
This showed that cGAS is crucial to the ALD disease process and, therefore, a potential drug target.
The team also found another possible target called Cx32, that they showed to make a difference in IRF3 activation and the death of liver cells.
Mice without the gene for coding Cx32 had drastically less liver damage after consuming excess alcohol. The scientists also saw beneficial effects if they inhibited the molecule.
Source: www.medicalnewstoday.com
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