A high-fat diet increases the likelihood of liver cancer

Researchers have found that in response to a high-fat diet, mature hepatocytes in the liver revert to an immature, stem cell-like state. This helps them survive the liver stress conditions caused by high fat intake, but, in the long term, it makes them more likely to become carcinogenic.

“If liver cells are forced to continually deal with a stressor, such as a high-fat diet, they will do things that help them survive, but at the cost of increasing their susceptibility to developing tumors.”says one of the authors, Alex Shalek, director of the Institute of Medical Engineering and Sciences at MIT.

The researchers also identified several genetic transcription factors that appear to control this cellular reversal, which could help develop therapies aimed at preventing tumor development in high-risk patients.

What happens in a ‘stressed’ liver

Until now, it was known that a high-fat diet can cause inflammation and fat accumulation in the liver, a condition known as steatotic liver disease or fatty liver.

That disease, which can also be caused by a wide variety of metabolic stresses (such as high alcohol consumption), can lead to liver cirrhosis, liver failure, and eventually cancer.

With this work, the MIT researchers wanted to find out whatWhat exactly happens in liver cells when exposed to a high-fat dietin particular, which genes are turned on or off when the liver responds to this stressor.

In an experiment with mice, they fed the rodents a high-fat diet and performed single-cell RNA sequencing of their liver cells at key times as the liver disease progressed.

This allowed them to detect changes in gene expression as the mice progressed toward liver inflammation and ultimately tumor development.

The researchers discovered that, in a first phase, a high-fat diet caused hepatocytes (the most abundant cells in the liver) to activate genes that helped them survive in a stressful environment; but at the same time, these cells began to deactivate some genes essential for the normal functioning of hepatocytes, such as metabolic enzymes and secreted proteins.

Some of these changes occurred immediately, while others, such as decreased production of metabolic enzymes, occurred more gradually. Most of the mice on a high-fat diet ended up developing liver cancer by the end of the study.

The reason, according to the researchers, is that when cells are in a more immature state, they are more likely to become cancerous if a mutation occurs later.

The researchers also identified the genes that revert hepatocytes to an immature state, key to finding therapeutic targets.

Predict liver cancer progression

After identifying these changes in mice, the researchers tried to discover if something similar could be happening in human patients with liver disease. To do this, they analyzed data from liver tissue samples taken from patients in different stages, and from patients with liver disease but who had not yet developed cancer.

Studies with human tissues revealed a pattern similar to that observed in mice: the expression of genes necessary for normal liver function decreased over time, while genes associated with immature states increased.

Furthermore, they found that analyzing gene expression patterns allowed them to accurately predict patients’ survival outcomes.

Although the mice in this study developed cancer in about a year, the researchers estimate that in humans, the process continues over a longer period, possibly around 20 years. A figure that would vary depending on diet and other risk factors, such as alcohol consumption or viral infections, which can also favor the reversion of liver cells to an immature state.

Now, researchers want to see if any of the changes that occur in response to a high-fat diet can be reversed by returning to a normal diet or taking weight-loss medications, such as GLP-1 agonists.