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High-Fat Diet rewrites Liver Cell code, Increasing Cancer Risk
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A high-fat diet isn’t just about weight gain; it fundamentally rewrites the code within your liver cells, dramatically increasing the risk of cancer. New research from MIT reveals how these dietary changes can push liver cells into a precarious state, making them more vulnerable to tumor development.
How Fat Alters Liver Cells at a Molecular Level
The study illuminates a cellular shift where mature liver cells revert to a more primitive state, prioritizing survival over function and ultimately increasing cancer susceptibility.
- A high-fat diet forces liver cells to adapt, shifting them to a stem-cell-like state.
- This adaptation, while initially protective, increases the risk of cancer over time.
- Researchers identified key genes and transcription factors involved in this cellular transformation.
- similar changes were observed in human liver tissue samples.
Researchers discovered that repeated exposure to high-fat diets causes mature liver cells, called hepatocytes, to undergo a important change. Instead of maintaining their specialized function, these cells regress to a more primitive, stem-cell-like state. “If cells are forced to deal wiht 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,” explains Alex K. Shalek, director of the Institute for Medical Engineering and Sciences (IMES), the J. W.Kieckhefer Professor in IMES and the Department of Chemistry, and a member of the Koch Institute for Integrative Cancer Research at MIT, the Ragon Institute of MGH, MIT, and Harvard, and the Broad Institute of MIT and Harvard.
The Cellular Trade-Off: Survival vs. Function
This transformation allows the cells to better withstand the stress caused by excess fat,but it comes at a cost. As hepatocytes prioritize survival,they begin to shut down genes essential for normal liver function,including those involved in metabolism and protein secretion.”This really leads to a situation where the liver is less able to perform its normal functions, and that creates a perfect storm for cancer development,” says Tzouanas.
The researchers used a technique called single-cell RNA sequencing to analyze the gene expression patterns in liver cells of mice fed a high-fat diet. They found that the cells began to express genes typically associated with embryonic development and stem cells. This suggests that the cells were reverting to a more immature state. The team also identified two enzymes, HMGCS1 and HMGCS2, that appear to play a crucial role in this process. HMGCS1 is linked to non-alcoholic steatohepatitis (NASH), a severe form of steatotic liver disease. Another enzyme,HMGCS2,is currently being tested in clinical trials for the same condition. Researchers also highlighted the transcription factor SOX4, typically active during fetal development, as a promising target.
Human Liver Tissue Confirms Findings
To validate their findings, the researchers analyzed liver tissue samples from human patients at various stages of liver disease, including those without cancer. The results mirrored the observations in mice: a decline in genes responsible for normal liver function and an increase in genes associated with immature cell states. Furthermore, these gene expression patterns correlated with patient survival rates. “Patients who had higher expression of these pro-cell-survival genes that are turned on with high-fat diet survived for less time after tumors developed,” says Tzouanas. “And if a patient has lower expression of genes that support the functions that the liver normally performs, they also survive for less time.”
