New research from MIT published this week in *Cell* reveals a concerning link between high-fat diets and an increased risk of liver cancer, adding to growing evidence of the disease’s connection to lifestyle factors [[1]].The study demonstrates that sustained high-fat intake can cause mature liver cells to revert to a more primitive state, making them vulnerable to cancerous mutations. Researchers identified key genetic drivers of this cellular change, opening potential avenues for preventative therapies, while also observing similar patterns in human liver tissue samples [[2]].
A diet high in fat can alter liver cells, reverting them to an immature state and increasing their susceptibility to cancer, according to a new study from the Massachusetts Institute of Technology (MIT). The research, published Monday in the journal Cell, sheds light on how dietary choices can impact long-term health and potentially contribute to the development of liver cancer – a growing concern globally.
Researchers discovered that mature liver cells, known as hepatocytes, revert to a state resembling that of stem cells when exposed to a high-fat diet. This response helps the cells survive the stress caused by excessive fat intake, but ultimately makes them more prone to becoming cancerous over time.
“If liver cells are continually forced to cope with a stressor, like a high-fat diet, they will do things to help them survive, but at the cost of increasing their susceptibility to developing tumors,” said Alex Shalek, director of the Institute for Medical Engineering and Science at MIT, and one of the study’s authors.
The team also identified several genetic transcription factors that appear to control this cellular reversion, potentially paving the way for therapies aimed at preventing tumor development in high-risk individuals.
What Happens in a ‘Stressed’ Liver
It’s already known that a high-fat diet can lead to inflammation and fat accumulation in the liver, a condition called nonalcoholic fatty liver disease (NAFLD). This condition, which can also be caused by a variety of metabolic stresses – such as high alcohol consumption – can progress to cirrhosis, liver failure, and eventually, cancer.
The MIT researchers aimed to understand precisely what happens within liver cells when exposed to a high-fat diet, specifically which genes are activated or deactivated as the liver responds to this stressor.
In an experiment involving mice, the researchers fed the animals a high-fat diet and performed single-cell RNA sequencing on their liver cells at key points as the liver disease progressed. This allowed them to track changes in gene expression as the mice developed liver inflammation and, ultimately, tumors.
The study found that, initially, a high-fat diet prompted hepatocytes to activate genes that helped them survive in a stressful environment. Simultaneously, these cells began to deactivate genes crucial for normal hepatocyte function, including those responsible for metabolism and protein secretion.
Some of these changes occurred immediately, while others, like the decrease in metabolic enzyme production, developed more gradually. Ultimately, most of the mice on the high-fat diet developed liver cancer by the end of the study.
Researchers believe this is because cells in a more immature state are more likely to become cancerous if a mutation occurs. The identification of the genes driving hepatocytes back to an immature state is a key step toward finding potential therapeutic targets.
Researchers also sought to determine if similar changes occur in humans with liver disease. They analyzed data from liver tissue samples taken from patients at different stages of the disease, including those who had not yet developed cancer.
Analysis of human tissue revealed a similar pattern 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 these gene expression patterns allowed them to accurately predict patient survival rates.
While the mice in the study developed cancer within approximately a year, researchers estimate the process takes much longer in humans – potentially around 20 years. This timeline can vary depending on diet and other risk factors, such as alcohol consumption or viral infections, which can also contribute to the reversion of liver cells to an immature state.
The researchers are now investigating whether the changes observed in response to a high-fat diet can be reversed by returning to a normal diet or by using weight-loss medications, such as GLP-1 agonists.
