A high-fat diet is one of the strongest risk factors for liver cancer. New research from MIT sheds light on why this is the case and shows that a high-fat diet can fundamentally alter liver cells, increasing the likelihood of cancer development.
How a High-Fat Diet Triggers the Reversal of Liver Cells
The researchers discovered that mature liver cells, known as hepatocytes, undergo a significant change when the liver is repeatedly exposed to a high-fat diet. Hepatocytes are the main cells of the liver and make up the majority of its tissue. They perform central metabolic tasks by processing and storing sugars, fats and proteins, for example glucose in the form of glycogen. They also play a key role in detoxifying the body by breaking down alcohol, drugs and other harmful substances or converting them into excretable forms. Hepatocytes also produce important proteins for the blood, such as albumin and coagulation factors, and form bile, which is necessary for the digestion of fat. They also store vitamins and trace elements.
Instead of remaining fully specialized, these cells transform into a more primitive, stem cell-like state. This transformation allows them to better withstand the stress caused by excess fat, but also increases their susceptibility to cancer over time. “When cells are repeatedly confronted with a stressor such as a high-fat diet, they respond with actions that help them survive, but at the risk of increased susceptibility to tumorigenesis,” said Alex K. Shalek, director of the Institute for Medical Engineering and Sciences (IMES), J. W. Kieckhefer Professor at IMES and in the Department of Chemistry, and a member of the Koch Institute for Integrative Cancer Research at MIT, the Ragon Institute of MGH, MIT and Harvard, and the Broad Institute of MIT and Harvard.
The team also identified several transcription factors that appear to regulate this cellular change. These factors could ultimately serve as targets for drugs designed to reduce the risk of tumor formation in particularly susceptible individuals. Shalek, Ömer Yilmaz, associate professor of biology at MIT and a member of the Koch Institute, and Wolfram Goessling, co-director of the Harvard-MIT Program in Health Sciences and Technology, are the lead authors of the study, which was published in Cell. MIT doctoral student Constantine Tzouanas, former MIT postdoctoral fellow Jessica Shay and postdoctoral fellow Marc Sherman of Massachusetts General Brigham are the co-first authors of the paper.
Liver Cancer in Almost All Mice
A high-fat diet can cause inflammation and fat accumulation in the liver, leading to a condition known as steatotic liver disease. This is a disease in which fat accumulates in the liver cells. It is colloquially referred to as fatty liver. This disease can also be caused by long-term metabolic stress factors such as heavy alcohol consumption and can lead to liver cirrhosis, liver failure and ultimately cancer.
In this study, the researchers wanted to understand how liver cells respond at a molecular level when exposed to a high-fat diet, focusing on which genes become more or less active during prolonged stress. To study this process, the team fed mice a high-fat diet and analyzed the liver cells at key stages of disease development using single-cell RNA sequencing. This approach allowed them to track the changes in gene activity as the animals progressed from liver inflammation to tissue injury to cancer.
Early on, the hepatocytes began activating genes that help the cells survive in harsh conditions. These included genes that reduce the likelihood of programmed cell death and promote further cell growth. At the same time, genes that are essential for normal liver function, including those involved in metabolism and protein secretion, were gradually switched off. “This really looks like a trade-off, where what’s good for the survival of the individual cell in a stressful environment takes precedence over what the whole tissue should be doing,” Tzouanas said. Some of these genetic changes occurred rapidly, while others developed more slowly. The decline in the production of metabolic enzymes, for example, took place over a longer period of time. At the end of the study, almost all of the mice fed a high-fat diet had developed liver cancer.
Why Immature Liver Cells Promote the Development of Cancer
The researchers found that liver cells that are in a less mature state are more likely to become cancerous if a harmful mutation occurs later. “These cells have already activated the same genes that they need to become cancerous. They have already moved away from their mature identity, which would otherwise impair their ability to proliferate,” says Tzouanas. “Once a cell picks up the wrong mutation, it really takes off, and it already has a head start on some of these hallmarks of cancer.”
The study also highlighted several genes that appear to coordinate the return to an immature cell state. During the course of the research, a drug targeting one of these genes (thyroid hormone receptor) was approved to treat a severe form of steatotic liver disease known as MASH fibrosis. In addition, a drug that activates another enzyme identified in the study (HMGCS2) is currently being tested in clinical trials for the treatment of steatotic liver disease. Another promising target discovered through research is a transcription factor called SOX4. This factor is normally active during fetal development and in a limited number of adult tissues (but not in the liver), making its activation in liver cells particularly noteworthy.
Findings from Human Liver Disease
After finding these cellular changes in mice, the researchers investigated whether similar patterns occur in humans with liver disease. They analyzed liver tissue samples from patients at different stages of the disease, including people who had not yet developed cancer. The results largely mirrored the observations in mice. Over time, the genes required for normal liver function decreased, while genes associated with immature cell states increased. The researchers also found that these gene expression patterns can be used to predict patients’ chances of survival.
Patients who had higher expression of these pro-cell survival genes, which are activated by a high-fat diet, survived less long after tumors developed. And if a patient has a lower expression of genes that support the normal functions of the liver, they also survive less long. While the mice developed cancer within about a year, the researchers estimate that the same process likely takes place over a much longer period of time in humans, possibly around 20 years. The exact time frame may vary depending on diet and other risk factors, including alcohol consumption and viral infections, which can also cause liver cells to enter an immature state.
Can Nutritional Damage be Reversed?
The research team now plans to investigate whether the cellular changes caused by a high-fat diet can be reversed. Future studies will test whether a return to a healthier diet or the use of weight loss drugs such as GLP-1 agonists (lead to improved insulin sensitivity and lower blood glucose and fat levels. As a result, less fat enters the hepatocytes and fat that has already been stored can be reduced. This significantly relieves the liver cells) can restore the normal behavior of the liver cells. Overall, GLP-1 agonists can help to bring hepatocytes back closer to their normal functional behavior. However, whether they can bring about a complete regression of liver damage, particularly in advanced fibrosis or cirrhosis, is still the subject of current research. Further research will also be conducted to determine whether the transcription factors identified in the study could serve as effective drug targets to prevent damaged liver tissue from progressing to cancer.