New research from MIT demonstrates that prolonged high-fat diets push liver cells into a primitive state, increasing their vulnerability to cancer. By analyzing mice and human samples, scientists uncovered how these cellular changes prioritize survival over normal function, paving the way for tumors. The findings, published in Cell, highlight potential drug targets to mitigate this risk.
A high-fat diet not only burdens the liver with excess fat but also triggers profound changes in its cells, according to a study led by researchers at the Massachusetts Institute of Technology (MIT). Published on December 22 in the journal Cell, the work explains why fatty liver disease often leads to cancer by showing how hepatocytes—mature liver cells—revert to an immature, stem-cell-like state under chronic metabolic stress.
The team, including senior authors Alex K. Shalek, Ömer Yilmaz, and Wolfram Goessling, fed mice a high-fat diet and used single-cell RNA-sequencing to track gene activity as the animals progressed from inflammation to scarring and cancer. Early on, the cells activated genes for survival, such as those preventing cell death and promoting growth, while downregulating those for metabolism and protein 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 co-first author Constantine Tzouanas, an MIT graduate student.
By the study's end, nearly all mice had developed liver tumors. The immature state leaves cells primed for malignancy if mutations arise, as they already express cancer-promoting genes. "These cells have already turned on the same genes that they're going to need to become cancerous," Tzouanas explains.
Analysis of human liver samples confirmed similar shifts: elevated survival genes and reduced functional ones correlated with poorer survival after tumor development. In humans, this process may span about 20 years, influenced by factors like alcohol or infections.
The researchers identified transcription factors like SOX4 as potential targets. One related drug for thyroid hormone receptor has approval for advanced steatotic liver disease, while another for HMGCS2 is in trials. Future work will test if healthier diets or GLP-1 agonists can reverse these changes. "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," Shalek says.
Co-first authors include Jessica Shay and Marc Sherman. The study was funded by sources including the National Institutes of Health and MIT initiatives.
