NewsMakers
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.
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.
NewsMakers
Could your oral health be affecting fertility?
Chronic oral inflammation may impair female fertility by triggering a systemic immune response that affects the ovaries. A new study shows this leads to oxidative damage, reduced egg quality, disrupted follicle development and reduced live birth rate. These findings point to a potential biological link between oral health and unexplained infertility, opening new directions for future treatments.
A new study led by Prof. Michael Klutstein at the Hebrew University of Jerusalem and Prof. Asaf Wilensky at the Hebrew University-Hadassah Medical center and spearheaded by the students Dr. Paz Kles and Stephen Ameho has uncovered a striking biological link between chronic oral inflammation and female fertility, suggesting that conditions in the mouth may have far-reaching effects on reproductive health.
Published in the Journal of Dental Research, the study shows that persistent inflammation in the oral cavity can impair ovarian function, reduce egg quality, and ultimately lower fertility rates.
Researchers examined in a mouse model inflammation associated with dental implants, a common clinical scenario, and tracked how immune signals spread throughout the body. Their findings reveal that inflammation does not remain confined to the oral cavity but triggers a systemic immune response that reaches the ovaries.
The consequences were significant. Chronic oral inflammation in the animals was linked to increased levels of inflammatory cytokines in the ovaries, along with shifts in immune cell populations. This was accompanied by oxidative damage to ovarian tissue, impaired development of follicles, and reduced quality of oocytes.
These biological changes translated into measurable reproductive outcomes, with markedly reduced birth rates observed under inflammatory conditions in the animals.
The study also identified deeper cellular effects. Oocytes exhibited DNA damage and epigenetic alterations resembling those seen in reproductive aging, pointing to a possible mechanism by which inflammation accelerates the decline in fertility.
“Inflammation is often thought of as a localized response, but our findings show that it can have systemic consequences that extend as far as the reproductive system,” said Prof. Michael Klutstein. “This work suggests that chronic oral inflammation may be an underrecognized factor in female infertility, potentially contributing to cases that currently have no clear explanation.”
The findings add to growing evidence that oral health is closely linked to overall health. Chronic oral inflammatory conditions such as periodontitis are widespread and have already been associated with a range of systemic diseases.
The researchers note that further investigation in clinical settings will be essential to determine how these findings translate to patient care. If confirmed, the work could open new avenues for diagnosis and treatment, including the use of anti-inflammatory or antioxidant approaches to improve fertility outcomes.
NewsMakers
Maintaining a healthy heart may require regular doses of positivity
The findings of this study further point to the importance of attending to mental and behavioral health for cardiovascular disease prevention and cardiovascular health optimization.
Positive psychology interventions such as mindfulness, gratitude journaling and optimism training can consistently improve blood pressure, inflammation markers and other cardiovascular disease risk factors within a matter of weeks, a recent study found. However, since these benefits are associated with lifestyle changes such as eating healthier and greater physical activity, the researchers suggested that ongoing reinforcements may be needed to stay on course long term.
Rosalba (Rose) Hernandez, a professor of social work at the University of Illinois Urbana-Champaign, led a team that analyzed the findings of 18 randomized controlled trials that used positive psychological and mindfulness interventions to enhance mental or physical health.
The programs that the team reviewed included individual methods — such as structured telephone sessions, journaling with brief check-ins and digital platforms such as apps and text messaging — and interactive in-person group sessions, as well as hybrid formats that blended these with online tools and virtual meetings. Most of the programs consisted of weekly sessions and at-home activities that reinforced the skills taught, with the majority of programs lasting from six to 12 weeks, the team found.
In general, the programs included 50-200 adults with elevated cardiovascular risk factors such as uncontrolled hypertension, heart failure or other conditions. Typically, the participants were in their late 50s to mid-60s, and women comprised 35-55% of the samples across those studies that reported their participants’ gender, according to the researchers.
“In hypertension and postacute coronary syndrome cohorts, mindfulness-based programs delivered over an eight-week period reduced systolic blood pressure and lowered inflammatory markers such as high-sensitivity C-reactive protein and fibrinogen,” said Hernandez, who is a Fellow of the American Heart Association. “A 12-week spirituality-based digital intervention achieved one of the largest reductions — reducing systolic blood pressure measured with a standard cuff by 7.6 points, and central systolic pressure — which is measured in the aorta as it leaves the heart — by 4.1 points.”
In prior research on positive psychology interventions, scientists seldom defined the dose that was needed to obtain the beneficial effects, Hernandez said. She and the team members sought to clarify the frequency and duration that was most likely to improve individuals’ cardiovascular health.
Programs that had more frequent contact with their participants yielded the most consistent physiological benefits, underscoring the opportunity to embed positive psychological strategies into long-term cardiovascular care, Hernandez said.
The team found that the strongest behavioral improvements were achieved by an eight-week program delivered over WhatsApp that combined weekly sessions with daily microtasks, motivating participants to engage in greater physical activity, eat a healthier diet and take their medication as prescribed. A program that included motivational interviewing succeeded in increasing cardiac patients’ levels of physical activity by 1,800 steps a day and their medication adherence, while the mindfulness programs improved participants’ activity levels and diets only, according to the study.
“The therapeutic dose that was most consistently linked with improvements in blood pressure, inflammation and endothelial function was daily practice reinforced by weekly sessions over eight to 12-week periods,” Hernandez said. “Therapeutic dosing typically involved high-frequency dosing over this time period to obtain short-term physiologic benefits, while ongoing less-intensive contact may be needed to sustain behavioral change.”
Published in the journal Cardiology Clinics, the study was co-written by University of South Florida social work professor Soonhyung Kwon; Alyssa M. Vela, a professor of surgery and of psychiatry and behavioral sciences at Northwestern University Feinberg School of Medicine; and Katharine S. Edwards, a professor of cardiovascular medicine and of psychiatry and behavioral medicine at Stanford Medicine.
“The findings of this study further point to the importance of attending to mental and behavioral health for cardiovascular disease prevention and cardiovascular health optimization,” Vela said. “This speaks to the need for routine screening and integration of cardiac behavioral medicine to allow for access to important interventions.”
The current study adds to a growing body of research linking psychological well-being — including traits such as optimism, positive affect and gratitude — with cardioprotective benefits.
NewsMakers
Heart disease risk may start in the womb, study finds
Young adults whose mothers had high blood pressure during pregnancy — either pregnancy-associated hypertension, pre-eclampsia or eclampsia — had more signs of early arterial injury, higher blood pressure, higher body mass index and higher blood sugar than peers.
A child’s future heart health may be partially shaped before they are born, reports a new Northwestern Medicine study that found pregnancy complications are linked to poorer cardiovascular health in offspring more than 20 years later.
The study found that young adults whose mothers had high blood pressure during pregnancy — either pregnancy-associated hypertension, pre-eclampsia or eclampsia — had more signs of early arterial injury, higher blood pressure, higher body mass index and higher blood sugar than peers.
The authors said the study adds to growing evidence that cardiovascular risk may be transmitted across generations through a combination of biological, environmental and behavioral factors.
“That means we must make sure people maintain good health from childhood into young adulthood, so that if or when someone becomes a parent, they pass on the best opportunity for good health to their children,” said study senior author Dr. Nilay Shah, assistant professor of medicine in the division of cardiology at Northwestern University Feinberg School of Medicine.
How the study was conducted
Shah and colleagues evaluated nearly 1,350 mother-child pairs from the Future of Families and Child Well-Being Study, which enrolled mothers and children at birth between 1998 and 2000 across 20 U.S. cities. The children were then followed into adulthood.
Using delivery hospitalization records, the Northwestern scientists first identified whether mothers experienced pregnancy complications, including high blood pressure during pregnancy, gestational diabetes (high blood sugar during pregnancy) or preterm birth (before 37 weeks of pregnancy).
The three pregnancy complications are on the rise, and affect almost one in four pregnancies in the U.S.
The research team then analyzed cardiovascular health of offspring at age 22, using blood pressure measurements, blood testing, body mass index assessments and carotid artery ultrasounds to look for signs of artery injury.
Finally, the scientists compared participants with and without exposure to each pregnancy complication and adjusted for factors like income, education, difference in birth weight and smoking during pregnancy.
Key findings
At around age 22, participants whose mothers had high blood pressure during pregnancy had:
- Higher body mass index (+2.8 BMI points)
- Higher diastolic blood pressure (+2.3 mm Hg)
- Higher blood sugar levels (+0.2% HbA1c)
- Thicker artery walls (~0.02 mm)
While the difference in artery wall thickness may seem small, the study authors said it corresponds to roughly three to five years of additional vascular aging. That means arteries looked older and less healthy than expected, which raises the risk of future heart disease.
Other pregnancy complications also showed some long-term effect:
- Exposure to gestational diabetes was linked to worse blood pressure and some evidence of artery thickening
- Being born preterm was associated with higher blood sugar levels
‘Most heart disease is preventable’
With pregnancy complications on the rise in the U.S., Shah said the study provides compelling evidence that improving health before and during pregnancy could help reduce heart disease risk in the next generation.
“There is evidence that both parents’ health at the time of conception and during pregnancy influences a child’s health,” he said. “So, promoting health from an early age, like exercising regularly, eating healthfully, never smoking and getting enough sleep, is not just meant for an individual, but doing so may help future generations be healthier, too.”
Shah also emphasizes that risk is not destiny.
“The good news is that most heart disease is preventable,” he said. “If you experienced high blood pressure or high blood sugar during pregnancy, or your child was born early, it does not absolutely mean that your child will have worse health as adults. But I would encourage you to pay attention now to your child’s health behaviors.
“What children learn in childhood sets the stage for their health across their lives. If you are wondering whether your children’s behaviors are healthy, or are considering making a change, please speak with your child’s pediatrician for advice and guidance.”
Other Northwestern co-authors include Emily Lam, Abigail Gauen, Dr. Sadiya Khan, Alexa Freedman and Norrina Allen.
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