Healthcare (Commonwealth Union) – A high-fat diet is one of the leading contributors to the risk of liver cancer. New research from MIT explains how excessive dietary fat alters liver cells, making them more vulnerable to turning cancerous.
The study shows that when exposed to a fatty diet, fully developed liver cells, known as hepatocytes, can revert to a less mature, stem-like state. While this change helps the cells cope with the ongoing stress caused by high fat intake, it also increases their long-term likelihood of developing into cancer cells.
Alex K. Shalek, director of MIT’s Institute for Medical Engineering and Sciences and a senior researcher involved in the study indicate that if cells are repeatedly challenged by a stressor like a high-fat diet, they adapt in ways that promote survival, but this comes with a higher risk of tumor formation.
In addition, the team identified a group of transcription factors that seem to regulate this cellular reversal. These factors could become promising targets for future drugs designed to reduce cancer risk in people most vulnerable to the disease.
Shalek; Ömer Yilmaz, an associate professor of biology at MIT and member of the Koch Institute; and Wolfram Goessling, co-director of the Harvard–MIT Program in Health Sciences and Technology, served as the study’s senior authors. The findings were published in Cell. MIT doctoral student Constantine Tzouanas, former MIT postdoctoral researcher Jessica Shay, and Marc Sherman, a postdoc at Massachusetts General Brigham, are listed as co–first authors.
Diets high in fat can trigger inflammation and fat accumulation in the liver, leading to a condition known as steatotic liver disease. This disorder—also linked to prolonged metabolic stress such as excessive alcohol intake—can progress to cirrhosis, liver failure, and ultimately liver cancer.
In this study, the scientists set out to understand how liver cells respond at the molecular level when subjected to a high-fat diet. Specifically, they examined which genes are activated or suppressed as the liver adapts to sustained metabolic strain.
To investigate this, the team fed mice a high-fat diet and used single-cell RNA sequencing to analyse liver cells at critical stages of disease development. This approach enabled them to track shifts in gene activity as the animals moved from liver inflammation to fibrosis and, eventually, to cancer.
The researchers of the study indicated that when cells are in an increased immature state, it will look like that they have an increased chance to become cancerous if a mutation takes place later on.
“These cells have already turned on the same genes that they’re going to need to become cancerous. They’ve already shifted away from the mature identity that would otherwise drag down their ability to proliferate,” explained Tzouanas. “Once a cell picks up the wrong mutation, then it’s really off to the races and they’ve already gotten a head start on some of those hallmarks of cancer.”
The team also pinpointed a set of genes that seem to drive the shift of hepatocytes back into a less mature, stem-like state. During the course of the research, a drug aimed at one of these genes—the thyroid hormone receptor—received approval for treating a serious form of steatotic liver disease known as MASH fibrosis. In addition, a therapy that activates another identified enzyme, HMGCS2, has now entered clinical trials for steatotic liver disease.
The study also highlighted another potential target: a transcription factor called SOX4. This factor is typically active only during fetal development and in a limited number of adult tissues, and is not usually expressed in the liver.
After uncovering these changes in mice, the researchers investigated whether similar processes occur in humans with liver disease. They examined data from liver tissue samples taken from patients at various stages of the condition, as well as samples from individuals who had liver disease but had not yet gone on to develop cancer.
