A new study conducted by researchers from the Massachusetts Institute of Technology revealed that a high-fat diet can make the liver more susceptible to turning into cancerous cells, which makes a high-fat diet one of the biggest risk factors for liver cancer.
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The researchers found that in response to a high-fat diet, mature liver cells revert to an immature, stem cell-like state. This helps them survive the stressful conditions created by a high-fat diet, but in the long term increases the likelihood that they will turn into cancer cells.
“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 increasing their susceptibility to tumors,” says Alex Schalek, director of the Institute for Medical Engineering and Science (IMES), and the study’s lead researcher.
In the new study, the researchers wanted to know exactly what happens in liver cells when they are exposed to a high-fat diet — in particular, what genes are turned on or off when the liver responds to this long-term stress.
To achieve this, the researchers fed mice a high-fat diet and performed single-cell RNA sequencing of liver cells at key time points as liver disease progressed. This allowed them to observe changes in gene expression that occurred as the mice progressed from hepatitis, to tissue scarring, and eventually to cancer.
In the early stages of this development, researchers found that a high-fat diet stimulates hepatocytes, the most abundant cell type in the liver, to activate genes that help them survive under stressful environmental conditions. These genes include those that make them more resistant to programmed cell death and more able to reproduce.
The researchers have also identified several transcription factors that appear to control this decline, which they believe could make good drug targets to help prevent the development of tumors in high-risk patients.
“These cells began to turn off certain genes that are essential for normal liver cell function, including metabolic enzymes and secreted proteins. According to the researchers, this really looks like a trade-off, where what is good for the individual cell to survive in a stressful environment is prioritized at the expense of what the collective tissue has to do.”
Some of these changes occurred immediately, while others, including decreased production of metabolic enzymes, occurred gradually over a longer period. Almost all of the mice that ate the high-fat diet developed liver cancer by the end of the study.
When cells are in an immature state, they appear to be more likely to become cancerous if a mutation occurs later, researchers say.
The researchers also identified several genes that appear to coordinate changes that return liver cells to an immature state. During this study, a drug that targets one of these genes (the thyroid hormone receptor) was approved to treat a severe form of fatty liver disease called polymorphic steatohepatitis (MASH). Another drug that activates an identified enzyme (HMGCS2) is currently undergoing clinical trials to treat fatty liver disease.
Another potential target uncovered by the new study is a transcription factor called SOX4, which is normally only active during fetal development and in a few adult tissues (but not the liver).
The researchers now plan to study whether any of the changes that occur in response to a high-fat diet can be reversed by returning to a normal diet or by taking weight-loss medications such as glucagon-like peptide-1 (GLP-1) receptor agonists. They also hope to study whether any of the transcription factors they identified could be a suitable target for drugs that might help prevent diseased liver tissue from turning into cancer.
