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Hepatocyte mutations linked to liver diseases

Thursday October 14th 2021

DNA mutations in liver cells lead to metabolism and insulin sensitivity in patients with liver disease, a new study has found.

The study, from the Wellcome Sanger Institute, the Cancer Research UK Cambridge Institute, the Cancer Grand Challenges Mutographs team, identified that the five mutations are specific to liver disease that is associated with obesity, type 2 diabetes, and chronic alcohol consumption.

Their findings provide a deeper understanding about the role three of them play in the disordered fat metabolism seen in non-alcoholic fatty liver disease (NAFLD) and chronic alcohol consumption.

The research, which is published in Nature, shows the mutations reduce the sensitivity of liver cells to insulin. Resistance to insulin activity is the hallmark of type 2 diabetes.

They say this demonstrates that acquired mutations could impair the liver’s ability to respond normally to dietary sugars and fats.

The new research analysed 1590 genomes from 34 patient liver samples, including healthy livers and those with liver disease. The team identified five hepatocytes that are mutated in patients who had liver disease, three of which have a direct impact on how liver cells metabolise fat and respond to insulin.

The identified cells that have mutations do not react to insulin signalling and do not take up the fats, which enables them to escape the damage caused by storing excess fat.

While the mutations are beneficial to the individual liver cell, they may impair its ability to contribute to the function of the liver as a whole.

Many of the patients had multiple independent mutations in metabolism genes and in some this led to mutations collectively impacting up to 15-25% of the entire liver.

The researchers found that the same metabolism gene was often recurrently mutated within an individual patient’s liver, but between different patients, the pattern of mutations was different.

This, they say, suggests it might be possible to split liver diseases into different subgroups defined by their patterns of mutations.

First author Dr Stanley Ng, postdoctoral fellow at the Wellcome Sanger Institute, said: “Liver disease is a complex disease that often sits at the centre of other issues and conditions such as obesity and type 2 diabetes. However, the relationship between these diseases is poorly understood.

“While further studies are needed to understand the genetic links between these conditions, and what the clinical consequences of the mutations are for our patients, our research leads to fascinating new understanding of systemic diseases and how to diagnose, manage, and treat them.”

Senior author Dr Matthew Hoare, advanced clinician scientist at the Cancer Research UK Cambridge Institute and member of the CRUK Cambridge Centre Early Detection Programme, added: “Understanding the role of these, and other, mutations in liver disease could help identify those who will be at higher risk of future complications, such as metabolic issues or liver cancer.

“Interestingly, none of the mutations in metabolism genes were linked to the development of liver cancer, possibly because cancer cells are hungry for nutrients and these mutations may actually disrupt the cells’ ability to meet those metabolic demands. This information may prove useful in understanding the changes experienced by a liver cancer as it evolves from a background of chronic liver disease.”

Tags: Cancer | Diabetes | Internal Medicine | UK News

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