High-Fat Diets: Rewiring the Liver for Cancer

Not cautious about how much fat you eat in your foods every day? A novel MIT study found that a high-fat diet strains liver cells and can increase the likelihood of your liver cells becoming cancerous. 

By Julian Lau

Have you ever felt uneasy when you look at the fat content on nutritional labels, unsure how it might affect health? Researchers at MIT have linked a high-fat diet with long-term implications, including liver damage and increased cancer risk.

How can a high-fat diet lead to cancer?

For years, researchers have linked diets high in fat to steatotic liver disease (SLD). This condition involves dangerous fat buildup within the liver. Today, SLD is the most common chronic liver condition, affecting about 33 percent of the population in the Americas (see Saeed reference below for more SLD research). While SLD initially presents as benign, or harmless, it can progress to fatal liver failure and even cancer. 

But what is the biology behind how SLD transitions from a benign to fatal state? Constantine Tzouanas and fellow researchers at MIT formed a study to find out. 

The researchers monitored gene expression in mice fed a high-fat diet, a metabolic stressor. They focused on hepatocytes, as these are the most abundant cell type in the liver. Ultimately, they aimed to determine how genes respond to metabolic stress. 

Hepatocyte responses in the liver

Initially, the hepatocytes turned on genes that helped them survive the stressful environment induced by the high-fat diet. These genes made the hepatocytes more resistant to apoptosis, or cell death, and more likely to proliferate, or divide. However, crucial survival genes simultaneously turned off, but over a longer period of time. These turned-off genes were responsible for producing key metabolic enzymes and secreting proteins. This state of hepatocytes is described as immature, as it has shifted away from the state prior to the high-fat diet. 

According to Constantine Tzouanas, co-first author of the study, “This really looks like a trade-off prioritizing what’s good for the individual cell to stay alive in a stressful environment, at the expense of what the collective tissue should be doing.”

But how do these changes in gene expression translate to cancer? The researchers suggest it is because the immature state of hepatocytes are more likely to become cancerous if mutations occur. These cells have already activated genes in the immature state needed for proliferation, which, in cancer, is the hallmark. Resultingly, when a cell picks up a mutation, the immature hepatocyte has a head start on the hallmarks of cancer. In the study, nearly all of the mice eventually developed liver cancer. 

Do these results translate to humans?

Following the study in mice, the researchers attempted to see if the same things were happening in human cells. Through human hepatocyte analysis, they found a very similar pattern. Genes associated with immature cells skyrocketed while the expression of genes for normal liver function decreased.

However, there are key differences between the cancer progression in hepatocytes between mice and humans. Mice developed cancer within a year or so, while the researchers estimate human hepatocytes to develop cancer over a much longer span, around 20 years. 

Several genes have been identified by the researchers that appear to trigger the immature state of hepatocytes. These genes are potential targets for future therapeutic drugs. Such drugs could prevent SLD and limit cancer progression.

More Diet Research: Paleo Diet is Dangerous, Expert Warns

How can we prevent this?

The clearest path forward is prevention. Simple lifestyle measures can significantly limit SLD development that would be due to long-term metabolic stresses. For starters, limiting alcohol consumption and reducing chronic stressors in our lives would be strong first measures in preventing SLD. To target the root of cancer development from SLD, dietary measures that address a high-fat diet are most effective. Curbing processed foods and saturated fats is a vital safeguard.

Ultimately, the fight against SLD is won in everyday decisions. From choosing to add a little less butter to our bread, to picking fat-free products, every choice matters. By shifting our focus from reactive treatments to proactive management, we can address the consequences of SLD before it has the chance to destroy our health.

This study was published in the peer-reviewed journal Cell.

References

‌Saeed, S., Burnside, J., Wen, C., Rapino, C., Patel, K., Ramji, A., Swain, M., & Sebastiani, G. (2025). Call to action: integrating steatotic liver disease into public health strategies in Canada. The Lancet Regional Health – Americas, 52, 101278. https://doi.org/10.1016/j.lana.2025.101278

Tzouanas, C. N., Shay, J. E. S., Sherman, M. S., Rubin, A. J., Mead, B. E., Dao, T. T., Tao, J., Lehrich, B. M., Eng, G., Patterson-Fortin, J., Butzlaff, T., Mana, M. D., Kolb, K. E., Walesky, C., Pepe-Mooney, B. J., Smith, C. J., Prakadan, S. M., Ramseier, M. L., Tong, Y. E., … Shalek, A. K. (2026). Hepatic adaptation to chronic metabolic stress primes tumorigenesis. Cell, 189(2), P435–460.e28. https://doi.org/10.1016/j.cell.2025.11.031

Featured image “Chopping Butter” by Justin Marx on Flickr, licensed under CC BY-NC-SA 2.0.

The information contained in this article is for educational and informational purposes only and is not intended as health or medical advice. Always consult a physician or other qualified health provider regarding any questions you may have about a medical condition or health objectives.