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MIT study: High-fat diets make liver cells more likely to become cancerous

Fatty diet rewires liver cells and makes them more prone to becoming cancerous.

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One of the biggest risk factors for developing liver cancer is a high-fat diet. A new study from MIT reveals how a fatty diet rewires liver cells and makes them more prone to becoming cancerous.

The researchers found that in response to a high-fat diet, mature hepatocytes in the liver revert to an immature, stem-cell-like state. This helps them to survive the stressful conditions created by the high-fat diet, but in the long term, it makes them more likely to become cancerous.

“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 increased susceptibility to tumorigenesis,” says 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 researchers also identified several transcription factors that appear to control this reversion, which they believe could make good targets for drugs to help prevent tumor development in high-risk patients.

Shalek; Ömer Yilmaz, an MIT associate professor of biology and a member of the Koch Institute; and Wolfram Goessling, co-director of the Harvard-MIT Program in Health Sciences and Technology, are the senior authors of the study, which appears today in Cell. MIT graduate student Constantine Tzouanas, former MIT postdoc Jessica Shay, and Massachusetts General Brigham postdoc Marc Sherman are the co-first authors of the paper.

Cell reversion

A high-fat diet can lead to inflammation and buildup of fat in the liver, a condition known as steatotic liver disease. This disease, which can also be caused by a wide variety of long-term metabolic stresses such as high alcohol consumption, may lead to liver cirrhosis, liver failure, and eventually cancer. 

In the new study, the researchers wanted to figure out just what happens in cells of the liver when exposed to a high-fat diet — in particular, which genes get turned on or off as the liver responds to this long-term stress.

To do that, the researchers fed mice a high-fat diet and performed single-cell RNA-sequencing of their liver cells at key timepoints as liver disease progressed. This allowed them to monitor gene expression changes that occurred as the mice advanced through liver inflammation, to tissue scarring and eventually cancer.

In the early stages of this progression, the researchers found that the high-fat diet prompted hepatocytes, the most abundant cell type in the liver, to turn on genes that help them survive the stressful environment. These include genes that make them more resistant to apoptosis and more likely to proliferate.

At the same time, those cells began to turn off some of the genes that are critical for normal hepatocyte function, including metabolic enzymes and secreted proteins.

“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,” Tzouanas says.

Some of these changes happened right away, while others, including a decline in metabolic enzyme production, shifted more gradually over a longer period. Nearly all of the mice on a high-fat diet ended up developing liver cancer by the end of the study.

When cells are in a more immature state, it appears that they are more likely to become cancerous if a mutation occurs later on, the researchers say.

“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,” Tzouanas says. “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 researchers also identified several genes that appear to orchestrate the changes that revert hepatocytes to an immature state. While this study was going on, a drug targeting one of these genes (thyroid hormone receptor) was approved to treat a severe form of steatotic liver disease called MASH fibrosis. And, a drug activating an enzyme that they identified (HMGCS2) is now in clinical trials to treat steatotic liver disease.

Another possible target that the new study revealed is a transcription factor called SOX4, which is normally only active during fetal development and in a small number of adult tissues (but not the liver).

Cancer progression

After the researchers identified these changes in mice, they sought to discover if something similar might be happening in human patients with liver disease. To do that, they analyzed data from liver tissue samples removed from patients at different stages of the disease. They also looked at tissue from people who had liver disease but had not yet developed cancer.

Those studies revealed a similar pattern to what the researchers had seen in mice: The expression of genes needed for normal liver function decreased over time, while genes associated with immature states went up. Additionally, the researchers found that they could accurately predict patients’ survival outcomes based on an analysis of their gene expression patterns.

“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,” Tzouanas says. “And if a patient has lower expression of genes that support the functions that the liver normally performs, they also survive for less time.”

While the mice in this study developed cancer within a year or so, the researchers estimate that in humans, the process likely extends over a longer span, possibly around 20 years. That will vary between individuals depending on their diet and other risk factors such as alcohol consumption or viral infections, which can also promote liver cells’ reversion to an immature state.

The researchers now plan to investigate whether any of the changes that occur in response to a high-fat diet can be reversed by going back to a normal diet, or by taking weight-loss drugs such as GLP-1 agonists. They also hope to study whether any of the transcription factors they identified could make good targets for drugs that could help prevent diseased liver tissue from becoming cancerous.

“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.

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Beauty & Fashion

Redefining aesthetics: From anti-aging to healthy aging

Growing attention is now being given to healthy aging, understanding how the entire face changes over time, preserving facial harmony, and helping people continue to look like themselves.

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For decades, “anti-aging” has defined the beauty and aesthetics conversation, promising to erase wrinkles and reverse the signs of time. Today, that conversation is shifting.

Aging is no longer just about looking younger. Growing attention is now being given to healthy aging, understanding how the entire face changes over time, preserving facial harmony, and helping people continue to look like themselves.

A review published in Facial Plastic Surgery, The Anatomy of the Aging Face: A Review, describes aging as changes across bone, ligaments, muscles, fat, and skin. Another review in Aesthetic Surgery Journal, The Facial Aging Process From the “Inside Out”, explains how changes beneath the surface eventually become visible on top.

Studies in Plastic and Reconstructive Surgery show facial fat is organized into distinct anatomical compartments that can lose volume and shift position over time, altering facial shape and balance.

For multi-awarded aesthetic physician Dr. James Co, founder of Cosma Institute and Architect of Aesthetic Confidence, these findings are the reason aesthetic care must start with understanding, not just treating.

“Aging is not a disease we need to cure,” Co said. “It is a biological process. As physicians, our role is to understand what is changing beneath the surface, how those changes differ from person to person, and whether intervention is appropriate in the first place.”

“When you only look at the wrinkle, you are looking at the surface of a much bigger anatomical process,” he added. “The face ages as a system. Good assessment means understanding what is happening underneath before deciding what should be done on the surface.”

Part of that understanding is recognizing that no two faces age the same way. Two people can be the same age and experience aging very differently. Genetics, skeletal structure, fat distribution, skin characteristics, sun exposure, lifestyle, and environmental factors all influence how aging presents.

“Two patients can be the same age and come to me with completely different anatomy, lifestyles, concerns, and goals,” Co said. “Why would we expect their treatment plans to look exactly the same?”

This is where healthy aging broadens the conversation — from fixing isolated signs to looking at the face as a whole and listening to what the individual actually wants.

“Someone can want to look refreshed without wanting to look 20 years younger,” Co said. “Those are completely different goals.”

Rather than trying to freeze one version of the face forever, healthy aging acknowledges that the face will continue to change. As different structures change at different rates, the relationship between features evolves. Facial harmony is therefore not fixed.

“You cannot freeze one version of your face forever,” Co said. “But you can understand how the face is changing and make decisions that respect its natural proportions and your identity.”

In the age of social media, where aesthetic treatments are highly visible, Co cautions against self-diagnosis.

“Patients should not have to diagnose themselves from social media,” he said. “You might recognize a concern, but deciding why it is happening and what should be done about it requires proper assessment.”

The shift is also about how people feel, not just how they look. A 2022 review on minimally invasive facial aesthetic procedures found studies are increasingly looking beyond physical changes to include satisfaction with appearance and aspects of psychological and social well-being, while noting that evidence still needs careful interpretation.

For Co, this reinforces that success is not always about looking dramatically younger.

“We need to ask whether the result makes sense for the patient, whether expectations were met, and whether we preserved the things that make that person recognizable,” he said. “I would rather someone tell my patient, ‘You look well,’ than immediately ask, ‘What did you have done?'”

At Cosma Institute, Co applies this consultation-led philosophy through individualized assessment, facial harmony, medical judgment, and patient education. Having trained aesthetic practitioners across Southeast Asia and Europe, he advocates for natural-looking outcomes that respect the characteristics already present in each face — an approach that recently earned him two awards at the Merz Aesthetics Tala Awards.

For Co, the evolution of aesthetic medicine is not about having more tools, but knowing when to use them — and when not to.

“Aging cannot be stopped, and I don’t think that should be the promise,” he said. “What we can do is understand it better. We can look at the science, understand the anatomy, listen to the patient, and make decisions that allow them to age while still looking recognizably like themselves.”

For Co, healthy aging begins not with fighting age, but with understanding it.

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The look and feel of your neighborhood may affect your sleep

Those living in neighborhoods rated as having a stronger sense of safety tended to sleep longer, and that this rating appeared to be shaped by the streetscape.

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Your neighborhood’s “streetscape”—the physical environment of your street—is something that you have probably never consciously thought about, despite seeing it every day. But what if the streetscape was affecting you on a subconscious level and disrupting your sleep? 

This intriguing question is posed by the findings of a study led by Professor Daisuke Matsushita of the Graduate School of Human Life and Ecology at Osaka Metropolitan University. The research team used AI to analyze more than 200,000 Google Street View images to identify visual neighborhood characteristics. They then linked these characteristics to the self-reported sleep of 1,089 working adults living on the lower floors of apartments in Tokyo, who were most likely to be affected by the streetscape.  

They found that those living in neighborhoods rated as having a stronger sense of safety tended to sleep longer, and that this rating appeared to be shaped by the streetscape. Generally, people slept longer in areas with lots of greenery, such as leafy trees, on the street. Similarly, high “enclosure”—meaning many tall vertical buildings and few wide-open spaces—was also associated with longer sleep and fewer insomnia symptoms. 

However, the study also made a surprising finding. The researchers found that highly walkable streetscapes, such as those with more sidewalks and traffic signs, were associated with a lowered sense of safety and shortened sleep duration.  

This suggests that walkability does not always represent a reassuring environment. Instead, a possible explanation is that streets with extensive pedestrian infrastructure are often busier, more crowded, and used by more strangers, which may be perceived as less safe or less relaxing than quieter residential streets.  

“This study demonstrates the potential for evaluating streetscape characteristics across large geographic areas in a cost-effective manner,” Dr. Matsushita said. “Based on the technique used in this study, cities could potentially measure perceived safety, beauty, liveliness, and enclosure as well as pollution and noise.”  

“We hope that opening up this new perspective creates further possibilities for designing healthier neighborhoods,” he concludes.  

The findings were published in Building and Environment.

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Workout or nap? Either can help your sleepless brain, study finds

People who either completed 20 minutes of moderate-to-vigorous exercise or took a 90-minute nap performed about 22 per cent better on memory tests after 30 hours without sleep than those who did neither.

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A short workout or a nap can help protect memory after a sleepless night, a McGill University-led study has found.

Researchers found people who either completed 20 minutes of moderate-to-vigorous exercise or took a 90-minute nap performed about 22 per cent better on memory tests after 30 hours without sleep than those who did neither. The findings, published in Proceedings of the National Academy of Sciences (PNAS), point to practical ways to counter the effects of sleep deprivation.

“Sleep loss affects nearly every aspect of how we think and function, but many people can’t simply stop what they’re doing and get more sleep,” said senior author Marc Roig, Professor in McGill’s School of Physical and Occupational Therapy. “Our findings show that even a brief bout of exercise may help preserve one of our most important cognitive abilities.”

The study involved 54 healthy young adults who stayed awake for 30 consecutive hours under lab supervision. Participants were then assigned to one of three groups: a 20-minute cycling session, a 90-minute nap or a control condition. Three days later, researchers tested their memory for images they had viewed immediately after the intervention. Those who exercised or napped remembered significantly more images than participants who did neither.

Same result, different pathways

While the memory benefits were nearly identical, brain recordings revealed that exercise and napping helped in different ways.

Napping appeared to help the brain recharge, making it easier to take in and remember new information. Exercise, by contrast, helped the brain use its remaining resources more efficiently, without making participants feel more tired.

The findings could eventually inform fatigue-management strategies in workplaces where sleep loss is common and mistakes can have serious consequences, such as health care, transportation and emergency response.

“A nap isn’t always possible in the middle of a shift,” said first author Madhura Lotlikar, a doctoral candidate in McGill’s Department of Neurology and Neurosurgery. “Exercise is accessible, inexpensive and easy to implement. That makes it a promising tool to help people stay cognitively sharp when sleep is limited.”

The researchers emphasize that exercise cannot replace sleep, but it may help people function better when getting enough rest isn’t possible.

About the study

“Protecting episodic memory after sleep loss: Similar benefits of exercise and naps via distinct neural contributions” by Madhura Lotlikar and Marc Roig et al., was published in Proceedings of the National Academy of Sciences of the United States of America.

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