[ScienceDaily] Mutations in hepatocytes are associated with liver disease and fat metabolism

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For the first time, DNA mutations in hepatocytes have been identified that impact metabolism and insulin sensitivity in patients with liver disease. These mutations are specific to liver disease including obesity, type 2 diabetes, and alcoholism.

The study, from the Wellcome Sanger Institute, Cancer Research UK UK Cambridge, the Cancer Grand Challenges Mutographs team and collaborators, identified five genes that are mutated in people with liver disease and better understand the role of 3 of these genes. in dyslipidemia in nonalcoholic fatty liver disease (NAFLD) and alcoholism.

The study, published today (October 13, 2021) in the journal Nature, shows that these mutations reduce the sensitivity of liver cells to insulin, with insulin resistance a hallmark of type 2 diabetes. These findings demonstrate that mutations acquired during a person’s lifetime can impair the liver’s ability to respond normally to dietary sugars and fats.

In the future, knowing the type of gene mutation in a patient’s liver could help confirm the correct diagnosis. These mutations can also be used to describe different forms of liver disease, which can help select the right treatments for each disease group. In addition, while further research is needed, this study may provide the basis for a potentially new model for understanding how mutations in specific cell types contribute to systemic metabolic syndromes. system, such as diabetes.

Currently, there are an estimated 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 alcoholism, viral hepatitis and NAFLD, including obesity and type 2 diabetes.

The new study analyzed 1590 genomes from 34 patients’ liver samples, including healthy livers and those with liver disease. The team identified five genes in liver cells (hepatocytes), which are mutated in patients with liver disease. Three of these are genes that have a direct effect on how liver cells metabolize fat and respond to insulin.

When a lot of alcohol or calories are consumed, insulin signals the liver cells to receive, process, and store large amounts of fat. If this persists for a long time, this excess fat storage burden damages cells, leading to inflammation, chronic liver disease, and eventually scarring (cirrhosis) in the liver.

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Cells with mutations in the genes identified in the report do not respond to insulin signaling and therefore do not absorb fat. This prevents them from being damaged by excess fat storage, and allows these mutant cells to survive and grow. However, although these mutations benefit individual liver cells, they can reduce the ability of the cells to function in the liver as a whole.

Notably, many patients have multiple independent mutations in metabolic genes. In some patients, this leads to a mutation that generally affects 15-25% of the entire liver, and there are large numbers of hepatocytes carrying the mutation that can lead to organ-wide changes in the liver. Liver function.

In a patient’s liver, the same metabolic gene is often mutated over and over again. However, between different patients, the mutation pattern is different, suggesting that it may be possible to divide liver disease into different groups of diseases defined by the patterns of cellular mutations. With further studies, it may be possible to develop and incorporate new treatments for these subtypes.

Dr Stanley Ng, first author and Postdoctoral Fellow at the Wellcome Sanger Institute, said: “Hepatic disease is a complex disease that is often at the heart of other problems and conditions such as obesity and diabetes. type 2 diabetes. However, the relationship between these diseases is not clear. Although further studies are needed to understand the genetic link between these conditions and the clinical consequences of mutations in our patients, our study uncovers fascinating new insights. guide to systemic diseases and how to diagnose, manage, and treat them.”

Dr Matthew Hoare, lead author, Distinguished Clinical Researcher at Cambridge Cancer Research UK and a member of the CRUK Cambridge Center Early Detection Programme, said: “Understanding the role of factors These and other mutations in liver disease can help identify people who will be at high risk for future complications, such as metabolic problems or liver cancer. Interestingly, none of the mutations in the metabolic genes have been implicated in the development of liver cancer, possibly because cancer cells are starving for nutrients, and these mutations can actually disrupt the ability of the cancer cells to develop. meet the metabolic needs of the cell. This information can be helpful in understanding how liver cancer changes as it develops from chronic liver disease. ”

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Dr David Scott, Director of Cancer Grand Challenges at Cancer Research UK, said: “The Cancer Grand Challenges Mutographs research team is helping to improve our understanding of the link between mutations and cancer. letters. This research isn’t just about cancer, but it also helps us learn more about the role mutations play in other diseases, like liver disease. ”

Dr. Peter Campbell, lead author and Head of Cancer, Aging and Somatic Mutations, and Division Head at the Wellcome Sanger Institute and co-investigator of the Cancer Grand Challenges Mutographs group, said: Specific types of cells, such as liver cells, have not previously been suspected to be the biological cause of diseases like obesity and type 2 diabetes. This is the passion of science – we set out to study it. This study hopes to understand how liver cancer develops from chronic liver disease, but instead breathes new life into the research paradigm in the same genetic problem that the genes are acquired independently multiple times in the liver. , which makes up a significant portion of hepatocytes. Mutations can protect liver cells from toxicity, but only by allowing those cells to evade metabolic duties. ”

* Moon AM, Singal AG, Tapper EB. (2020) Contemporary epidemiology of chronic liver disease and cirrhosis. Clin Gastroenterol Hepatol. DOI: 10.1016 / j.cgh.2019.07.060.

** British Liver Trust Statistics.

Information sources:

Materials provided by Wellcome Trust Sanger Institute. Note: Content may have been modified in presentation and length.

References:

  1. Convergent somatic mutations in metabolism genes in chronic liver disease.

Stanley WK Ng, Foad J. Rouhani, Simon F. Brunner, Natalia Brzozowska, Sarah J. Aitken, Ming Yang, Federico Abascal, Luiza Moore, Efterpi Nikitopoulou, Lia Chappell, Daniel Leongamornlert, Aleksandra Ivovic, Philip Robinson, Timothy Butler, Mathijs A. Sanders, Nicholas Williams, Tim HH Coorens, Jon Teague, Keiran Raine, Adam P. Butler, Yvette Hooks, Beverley Wilson, Natalie Birtchnell, Huw Naylor, Susan E. Davies, Michael R. Stratton, Iñigo Martincorena, Raheleh Rahbari, Christian Frezza, Matthew Hoare, Peter J. Campbell. Nature, 2021;

DOI: https://www.nature.com/articles/s41586-021-03974-6

The article is translated and edited by ykhoa. org – please do not reup without permission!

Source: ScienceDaily

Link: https://www.sciencedaily.com/releases/2021/10/211013122736.htm

Author: Roxie Duong

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