when the liver faces repeated exposure to a high-fat diet, mature liver cells – called hepatocytes – undergo a significant change.They don’t stay fully specialized. Instead, they revert to a more primitive, stem-cell-like state. This helps them survive the stress of excess fat, but it also increases their vulnerability to becoming cancerous over time.

“if cells are forced to deal with a stressor, like a high-fat diet, repeatedly, they’ll adapt to survive.But this adaptation comes with an increased risk of tumor development,” explains Alex K. Shalek, director of the Institute for Medical Engineering and Sciences (IMES) and a professor at MIT.

The team pinpointed several transcription factors that regulate this cellular shift. These factors could become targets for drugs designed to lower tumor risk in vulnerable individuals.

The study, published in Cell on December 22, was led by Shalek, Ömer Yilmaz (MIT associate professor of biology), and Wolfram Goessling (co-director of the Harvard-MIT Programme in Health Sciences and Technology). Constantine Tzouanas, Jessica Shay, and Marc Sherman were co-first authors.

How Fatty Diets Trigger Liver Cell Reversion

High-fat diets cause inflammation and fat buildup in the liver, leading to steatotic liver disease. This can also result from long-term metabolic stress, such as heavy alcohol use, and can progress to cirrhosis, liver failure, and ultimately, cancer.

The researchers wanted to understand how liver cells respond at a molecular level to a high-fat diet. They focused on which genes become more or less active as the stress continues.

to investigate, they fed mice a high-fat diet and used single-cell RNA-sequencing to analyze liver cells at key stages of disease development. This allowed them to follow the changes happening within individual cells.