Hepatocyte mutations associated with liver disease and fat metabolism

This study came from the Wellcome Sanger Institute, the Cambridge Institute for Cancer Research, the Cancer Challenge muttographs team and collaborators.
It identified 5 mutated genes in patients with liver disease and identified 3 genes in non-alcoholic fatty liver disease.
(NAFLD) and the role of fat metabolism disorders seen in chronic alcohol consumption provide a deeper understanding
.

The study published today (October 13, 2021) in the journal Nature shows that these mutations reduce the sensitivity of liver cells to insulin, and resistance to insulin activity is a hallmark of type 2 diabetes
.

These findings suggest that mutations acquired during a person’s lifetime may impair the liver’s ability to respond normally to sugar and fat in the diet

In the future, understanding the patterns of liver gene mutations in patients can help determine the correct diagnosis
.

These mutation patterns can also be used to describe different subtypes of liver disease, and may help to match treatments for each group

Currently, it is estimated that there are approximately 1.
5 billion cases of chronic liver disease* worldwide, and liver disease is the third leading cause of premature death in the UK**
.

The most common causes of chronic liver disease are chronic alcohol consumption, viral hepatitis, and non-alcoholic fatty liver, the latter being related to obesity and type 2 diabetes

The new study analyzed 1,590 genomes from 34 patients’ liver samples, including healthy and liver disease
.

The research team found 5 mutated genes in liver cells (also known as hepatocytes) of patients with liver disease

When people consume large amounts of alcohol or calories, insulin sends signals to liver cells to allow them to ingest, process and store large amounts of fat
.

If this situation continues for a long time, the burden of storing these excess fats will damage the cells, leading to inflammation, chronic liver disease, and eventually liver scarring (cirrhosis)

The genetically mutated cells found in this paper do not respond to insulin signals and therefore do not absorb fat
.

This allows them to escape the damage caused by storing excess fat, and allows these mutant cells to survive and grow

It is worth noting that many patients have multiple independent mutations in metabolic genes
.

In some patients, this can cause mutations to collectively affect 15% to 25% of the entire liver.

In the liver of a single patient, the same metabolic gene often undergoes repeated mutations
.

However, the patterns of mutations are different between different patients, which suggests that liver diseases may be divided into different subgroups, defined according to their mutation patterns

The first author, Dr.
Stanley Ng, a postdoctoral researcher at the Wellcome Sanger Institute, said: "Liver disease is a complex disease.
It is often other problems and diseases such as obesity and type 2 diabetes.
the core
, however, the relationship between these disorders is unclear
.
Although more research is needed to understand the genetic link between these diseases and the clinical consequences for the patient's mutation, but our study is a systemic disease and how to diagnose , Management and treatment have brought fascinating new understandings
.
"

Dr.
Matthew Hoare is a senior clinical scientist at the Cambridge Institute for Cancer Research in the United Kingdom and a member of the Early Detection Program at the Cambridge Centre for Cancer Research in the United Kingdom.
He said: “Understanding the role of these and other liver disease mutations can help determine who will have metabolic The risk of problems or complications such as liver cancer is higher
.
” Interestingly, mutations in metabolic genes have nothing to do with the development of liver cancer.
This may be because cancer cells are very hungry for nutrients, and these mutations may actually destroy cells to satisfy these.
Ability to metabolize needs
.
This information may help to understand the changes in liver cancer that have evolved from the background of chronic liver disease
.
"

Dr.
David Scott, Cancer Challenge Director of Cancer Research UK, said: “The Cancer Challenge Mutographs team is helping to change our understanding of the link between mutations and cancer
.
This research 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, research leader of cancer, aging and somatic mutations, senior team leader of the Wellcome Sanger Institute, and co-investigator of the Mutographs team for the major cancer challenge, said: "In specific cell types (such as liver cells) The mutations obtained have never been suspected to be related to the biology of diseases such as obesity and type 2 diabetes
.
This is the joy of science.
We started this research with the hope of understanding liver cancer out of chronic liver disease, but finally propose an exciting new model.
The same gene activity has been independent in the liver many times, collectively accounting for a considerable part of the liver cells
.
Mutations may protect liver cells from toxicity, but this is only by allowing these cells to evade their metabolic duties
.
"

Journal Reference :

1. 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, Mathijler 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.
   Convergent somatic mutations in metabolism genes in chronic liver disease .
   Nature , 2021; DOI: 10.
   1038/s41586-021-03974-6