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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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For weight loss, where food comes from may matter as much as how it is processed

Processed and ultra-processed animal foods tended to track with weight gain, and minimally processed plant foods with weight loss, although these associations were weaker. Ultra-processed plant foods were not associated with weight change.

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Eating more meat, fish, eggs, and dairy products was associated with weight gain even when those foods were minimally processed, according to a study from the Physicians Committee for Responsible Medicine published in Nutrition Research. Minimally processed plant foods, such as fruits, vegetables, whole grains, and beans, showed the opposite pattern.

“Ultra-processed foods get most of the blame for weight gain, but our results suggest we also need to ask whether a food comes from a plant or an animal,” says lead author Hana Kahleova, MD, PhD, director of clinical research at the Physicians Committee. “A chicken breast is minimally processed. So is an apple. In our study, they did not move the scale in the same direction.”

The researchers analyzed data from a randomized crossover trial in which 62 adults with overweight followed a Mediterranean diet, rich in olive oil, fish, and nuts, and a low-fat vegan diet for 16 weeks each, separated by a four-week washout. Participants kept three-day diet records, and every food was classified by degree of processing, using the NOVA system, and by whether it came from a plant or an animal.

Compared with the Mediterranean diet, the vegan diet cut minimally processed animal foods by 135 grams per day more and raised minimally processed plant foods by 202 grams per day more. Processed animal and plant foods also fell more on the vegan diet. Across both diets, eating more minimally processed animal foods was linked to weight gain; this was the strongest association in the analysis and the only one to remain statistically significant after correction for multiple comparisons.

Processed and ultra-processed animal foods tended to track with weight gain, and minimally processed plant foods with weight loss, although these associations were weaker. Ultra-processed plant foods were not associated with weight change.

In the main trial, published in 2022, participants lost an average of 6 kilograms (about 13 pounds) on the vegan diet, with no change on the Mediterranean diet. Minimally processed plant foods are high in fiber and water and low in calorie density, which helps people feel full on fewer calories.

“If you want to lose weight, fill your plate with beans, vegetables, fruits, and whole grains, and leave the animal products off,” says Dr. Kahleova. “The degree of processing still matters, but it is not the whole story.”

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Mindfulness and self-compassion can alleviate premenstrual symptoms

It is estimated that PMS affects approximately 20-30% of  menstruating people, while PMDD impacts 3-8%. The scale of the problem is significant, yet the psychological factors that protect against the development of these symptoms have not been thoroughly investigated.

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A kind attitude toward oneself and practicing mindfulness can improve functioning in individuals who experience severe premenstrual symptoms, according to a study by psychologists from SWPS University and Jagiellonian University.

Premenstrual syndrome (PMS) and its more severe form, premenstrual dysphoric disorder (PMDD), cause distressing psychological and physical symptoms, including mood swings, fatigue, concentration difficulties, headaches, and muscle pain. These ailments occur during the second phase of the menstrual cycle and interfere with daily functioning, affecting education, work, relationships, and overall quality of life.

Up to 30 percent of women affected

It is estimated that PMS affects approximately 20-30% of  menstruating people, while PMDD impacts 3-8%. The scale of the problem is significant, yet the psychological factors that protect against the development of these symptoms have not been thoroughly investigated.

The study, published in “Psychology and Psychotherapy: Theory, Research and Practice”, is part of a broader project analysing potential mechanisms and factors that may protect against the onset of PMS and PMDD. In a new study, Rachela Antosz-Rekucka, PhD, a psychologist at the Institute of Psychology at SWPS University, and Katarzyna Prochwicz, PhD, a professor at the Institute of Psychology of the Jagiellonian University, analysed factors that might protect against the onset of severe premenstrual symptoms. They examined variables such as the sense of coherence, mindfulness skills, and self-compassion, and investigated their relationship with past trauma, perceived stress levels, and symptoms of premenstrual disorders.

The study involved 228 participants aged 18 to 52. They were asked about their past experiences with premenstrual symptoms, and a part of the group subsequently tracked their symptoms over the course of two menstrual cycles.

Self-compassion and mindfulness help alleviate symptoms

The results suggest that higher levels of certain psychological resources can moderate the negative effect of stress and trauma on the severity of menstrual cycle-related symptoms.

Specific psychological attitudes may noticeably reduce the impact of daily stress on the severity of premenstrual symptoms. These include a kind attitude toward oneself and the acceptance of difficult moments, known as self-compassion. This approach helps women to navigate the challenging phases of their cycle more easily, even during times of intense nervous tension, says Rachela Antosz-Rekucka of SWPS University, who conducted the study as part of her doctoral research at the Jagiellonian University.

Practicing mindfulness (directing one’s attention to the present moment without judgment or worry) can also offer relief. In the context of PMS and PMDD, refraining from judging one’s own emotional reactions is particularly helpful, as it prevents the magnification of perceived discomfort. Furthermore, individuals with a strong sense of coherence cope better with rising premenstrual stress.

Past trauma and premenstrual symptoms

For individuals with a history of trauma, the ability to precisely describe their internal states and feelings, combined with the capacity to avoid judging their own emotional reactions, can help mitigate the negative impact of that trauma on premenstrual symptoms.

Psychological resources boost stress resilience

The results of the study could be significant for many people who menstruate. These findings could pave the way for modern therapeutic programs based on approaches such as mindfulness training or self-compassion-focused therapy, potentially reducing the reliance on medication.

The study suggests that more understanding, mindful, and compassionate attitude towards oneself may benefit individuals with severe premenstrual symptoms. PMS and PMDD are chronic conditions, which is why interventions such as mindfulness-based therapy, compassion-focused therapy, or strategies oriented at enhancing the sense of coherence, may help individuals navigate their conditions more effectively, and possibly increase their overall quality of life, Rachela Antosz-Rekucka emphasises.

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Music can enhance the flavor of your food

The brain does not create flavor based solely on signals from the tongue.

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The moment we take a sip of our morning coffee or our first bite of lunch, the brain begins interpreting what we taste. Is it sweet? Sour? Or something else entirely?

But the brain does not create flavor based solely on signals from the tongue. That is the finding of a new study from the Department of Food Science, published in the scientific journal Scientific Reports.

“When music reaches the ears at the same time as we are eating, we can see that the brain responds more strongly than when taste is experienced without music,” says first author and postdoctoral researcher Alberte Baggesgaard Seeberg from the Department of Food Science.

Using brain scans, the researchers show that music can activate some of the same brain regions involved in processing taste.

“This tells us that flavour is not simply a property of food. Flavor is an experience created by the brain,” says senior author and associate professor Janice Wang.

A breakthrough in brain imaging

This is the first time researchers have used brain imaging to show what happens in the brain when it processes taste. In the study, they used functional magnetic resonance imaging (fMRI), which measures activity in different parts of the brain by detecting changes in blood flow.

“This allows us to move beyond simply asking people about their experiences, which has been the approach in previous studies. With brain scans, we gain a biological window into what happens when the senses interact,” says Alberte Baggesgaard Seeberg.

While participants lay in the scanner, their brain activity was measured under different conditions. In some cases, they listened only to music. In others, they tasted flavor solutions. In some trials, music and taste were presented simultaneously. This enabled the researchers to compare how the brain responds to sound and taste separately and in combination.

The results clearly showed that certain brain regions were more active when participants listened to music while tasting one of the two flavor solutions.

“We can see that flavor is constructed by the brain and not only by the taste buds. What determines flavor is not limited to what happens on the tongue. It emerges through the integration of multiple senses,” says Janice Wang.

The findings build on previous studies showing that music can enhance particular taste perceptions. For example, slow pop music with harmonious tones may enhance sweetness. Until now, however, this has only been investigated through behavioral studies in which participants rated flavours with and without music.

Shaping flavor experiences could improve wellbeing

According to the researchers, the new knowledge could be used to design better eating experiences in a range of settings, including restaurants, canteens and hospitals.

“For people who are at risk of malnutrition, something as simple as music could potentially improve the eating experience. There is a great deal we can do, often at very little cost, to improve quality of life for some people,” says Alberte Baggesgaard Seeberg.

Janice Wang is pleased that, after many years of research into flavour and sensory perception, the team can now present biological evidence of how the senses interact.

“We now have a new way of influencing flavor perception, creating a better meal experience and potentially a better overall experience, without necessarily changing the food itself,” she says.

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