High-Fat Diet Drives Liver Cells Toward Cancerous State, Study

A new study from MIT reveals how a high-fat diet alters liver cells, making them more prone to cancer. The researchers found that in response to fatty conditions, mature hepatocytes revert to an immature, stem-cell-like state. This adaptation helps the cells survive stressful conditions but increases their susceptibility to cancer over time.

“If cells are forced to deal with a stressor, such as a high-fat diet, over and over again, they will do things that will help them survive, but at the risk of increased susceptibility to tumorigenesis,” says Alex K. Shalek, a senior author of the study published in Cell.

To explore how fatty diets affect the liver, the team fed mice a high-fat diet and used single-cell RNA sequencing to track gene expression over time. They observed that hepatocytes switched on genes promoting survival and proliferation, while turning off genes responsible for metabolic functions and secretion. “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,” says lead author Constantine Tzouanas. These changes occurred gradually, and nearly all mice on the high-fat diet developed liver cancer.

The study found that reverting to an immature cell state gives hepatocytes an early advantage for malignant transformation. “These cells have already turned on the same genes that they’re going to need to become cancerous,” Tzouanas explains. “Once a cell picks up the wrong mutation, then it’s really off to the races.”

Several genes were identified as orchestrators of this reprogramming, including transcription factors such as SOX4, which is typically active only during fetal development. Some of these targets already have links to existing or experimental therapies for steatotic liver disease, including drugs that affect the thyroid hormone receptor and the enzyme HMGCS2. 

The researchers confirmed similar gene expression trends in liver tissue from human patients at various disease stages. Patients with higher expression of pro-survival genes and lower expression of normal liver-function genes had shorter survival times after tumor onset.

Although mice developed cancer within about a year, the researchers suggest that in humans, this process unfolds over decades and may be influenced by diet, alcohol, or viral infections. Future work will test whether reversing diet or using weight-loss drugs can restore healthy liver function. “We now have all these new molecular targets and a better understanding of what is underlying the biology, which could give us new angles to improve outcomes for patients,” says Shalek.