Study identifies DNA mutations linking liver disease to obesity and diabetes



For the first time, DNA mutations in liver cells have been identified that impact metabolism and insulin sensitivity in patients with liver disease. These mutations are specific to liver disease associated with obesity, type 2 diabetes and chronic alcohol consumption.

The study, from the Wellcome Sanger Institute, Cancer Research UK Cambridge Institute, Cancer Grand Challenges Mutographs team and collaborators, identified five mutated genes in people with liver disease and provided insight the role of three of them. in fat metabolism disorders seen in non-alcoholic fatty liver disease (NAFLD) and chronic alcohol consumption.

The research, published today (13e October 2021) to Nature, shows that these mutations reduce the sensitivity of liver cells to insulin, resistance to insulin activity being the hallmark of type 2 diabetes. These results demonstrate that mutations acquired during the life of a person could impair the liver’s ability to respond normally to dietary sugars and fats.

In the future, understanding the pattern of genetic mutations in a patient’s liver could help identify the correct diagnosis. These patterns of mutations could also be used to characterize different subtypes of liver disease, possibly helping to match treatments to each group. Additionally, while more studies are needed, this research could lead to a potential new model for understanding how mutations in specific cell types can contribute to systemic metabolic diseases, such as diabetes.

Currently, it is estimated that there are around 1.5 billion cases of chronic liver disease worldwide, with liver disease being the third leading cause of premature death in the UK. The most common causes of chronic liver disease are chronic alcohol use, viral hepatitis, and NAFLD, which is linked to obesity and type 2 diabetes.

This new research analyzed 1,590 genomes from 34 liver samples from patients, including healthy livers and those with liver disease. The team identified five genes in liver cells, also called hepatocytes, that are mutated in patients with liver disease. Three of them were genes that have a direct impact on how liver cells metabolize fat and respond to insulin.

When there is a high consumption of alcohol or calories, insulin signals the liver cells to absorb, process and store a large amount of fat. If this continues for long periods of time, the burden of storing this excess fat damages cells, leading to inflammation, chronic liver disease, and ultimately scarring (cirrhosis) of the liver.

Cells that have mutations in the genes identified in the article do not respond to insulin signaling and therefore do not absorb fat. This allows them to escape the damage caused by the storage of excess fat and allows these mutated cells to survive and thrive. However, while these mutations provide a benefit to the individual liver cell, they can interfere with that cell’s ability to contribute to the function of the liver as a whole.

Remarkably, many patients had multiple independent mutations in the genes for metabolism. In some patients, this has led to mutations collectively affecting up to 15-25% of the entire liver, and having such a high number of mutated liver cells could lead to changes in liver function. at the organ level.

In a patient’s liver, the same metabolic gene was often mutated repeatedly. However, between different patients the pattern of mutations was different, suggesting that it might be possible to divide liver disease into different subgroups defined by their patterns of mutations. With further research, it may be possible to develop and associate new treatments with these subgroups.

Liver disease is a complex disease that is often at the center of other problems and conditions such as obesity and type 2 diabetes. However, the relationship between these diseases is poorly understood. While more studies are needed to understand the genetic links between these conditions and what the clinical consequences of mutations are for our patients, our research is leading to a fascinating new understanding of systemic diseases and how to diagnose, manage them. and process them. “

Dr Stanley Ng, Senior Author and Postdoctoral Fellow, Wellcome Sanger Institute

Dr Matthew Hoare, senior author, advanced clinician scientist at Cancer Research UK Cambridge Institute and member of the early detection program at CRUK Cambridge Center, said: “Understanding the role of these and other mutations in liver disease could help. to identify those who are at higher risk of future complications, such as metabolic problems or liver cancer.It is interesting to note that none of the mutations in the metabolism genes have been linked to the development of breast cancer. liver, perhaps because cancer cells are hungry for nutrients and these mutations can actually disrupt the cells’ ability to meet these metabolic demands. This information can be useful in understanding the changes that liver cancer undergoes as it progresses from a background of chronic liver disease. “

Dr David Scott, Director of Cancer Grand Challenges at Cancer Research UK, said: “The Cancer Grand Challenges Mutographs team is helping to transform our understanding of the link between mutations and cancer. This study shows that the scope of this work goes beyond cancer, including helping us learn more about the role of mutations in other diseases, such as liver disease. “

Dr Peter Campbell, senior author and head of Cancer, Aging and Somatic Mutation, and Senior Group Leader at the Wellcome Sanger Institute, and co-investigator of the Cancer Grand Challenges Mutographs team, said: “Acquired mutations in cell types specific, such as liver cells, have not previously been suspected of contributing to the biology of diseases such as obesity and type 2 diabetes. That’s the joy of science – we started this study in the ‘hope to understand how liver cancer emerges from chronic liver disease, but instead offers an exciting new model in which the same genetic event is acquired multiple times independently in the liver, collectively representing a sizable fraction of liver cells . The mutations could protect liver cells from toxicity, but only by allowing these cells to bypass their metabolic functions. “


Wellcome Trust Sanger Institute

Journal reference:

Ng, SWK, et al. (2021) Convergent somatic mutations in metabolic genes in chronic liver disease. Nature.


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