A new study from the Massachusetts Institute of Technology (MIT), published in the journal Cell, has found that a diet high in fat alters liver cells, reverts them to an immature state, and makes them more prone to becoming cancerous.
Researchers discovered that in an initial 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. At the same time, these cells began to deactivate some fundamental genes for normal hepatocyte function, such as metabolic enzymes and secreted proteins.
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. Most of the mice on a high-fat diet developed liver cancer by the end of the study.
"If liver cells are forced to continuously deal with a stress factor, 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," states one of the authors, Alex Shalek, director of MIT's Institute for Medical Engineering and Science.
After identifying these changes in mice, the researchers sought to discover if something similar might be happening in human patients with liver disease. This data would vary depending on diet and other risk factors, such as alcohol consumption or viral infections, which can also promote the reversion of liver cells to an immature state. This helps them survive the stressful liver conditions caused by high fat intake, but in the long term, it makes them more prone to becoming cancerous.
The researchers found that in response to a high-fat diet, mature hepatocytes in the liver revert to an immature state, similar to that of stem cells.
Until now, it was known that a high-fat diet can cause inflammation and fat accumulation in the liver, a condition known as fatty liver disease or hepatic steatosis. With this work, MIT researchers wanted to find out exactly what happens to liver cells when they are exposed to a high-fat diet, particularly which genes are activated or deactivated when the liver responds to this stressor.
The researchers also identified the genes that revert hepatocytes to an immature state, which is key to finding therapeutic targets. This allowed them to detect the changes that occurred in gene expression as the mice progressed toward liver inflammation and ultimately tumor development. To do this, they analyzed data from liver tissue samples taken from patients at different stages, and from patients with liver conditions who had not yet developed cancer.
In one experiment, the researchers fed the rodents a high-fat diet and performed single-cell RNA sequencing of their liver cells at key moments as the liver disease progressed. This disease, which can also be caused by a wide variety of metabolic stresses (such as high alcohol consumption), can lead to cirrhosis, liver failure, and ultimately, cancer.
The researchers also identified several genetic transcription factors that seem to control this cellular reversion, which could help develop therapies aimed at preventing tumor development in high-risk patients. Now, the 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 by taking weight-loss medications, such as GLP-1 agonists.
Studies on 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. Although the mice in this study developed cancer in about a year, the researchers estimate that in humans, the process takes a longer period, possibly around 20 years. Additionally, they saw that analyzing the gene expression patterns allowed them to accurately predict patient survival outcomes. Some of these changes occurred immediately, while others, such as the decrease in metabolic enzyme production, took place more gradually.
