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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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Study finds low-dose eye drops successful in managing adult myopia for 24 hours

A single low-dose atropine eye drop can produce daylong effects in managing myopia, or nearsightedness.

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Groundbreaking research from the University of Houston shows that a single low-dose atropine eye drop can produce daylong effects in managing myopia, or nearsightedness, which affects roughly one-third of U.S. adults.   

Professor of Optometry Lisa Ostrin and postdoctoral researcher Barsha Lal are reporting that even one drop in the eye of low-dose atropine (0.01%–0.1%) produces clear changes in pupil size and focusing ability that persist for at least 24 hours. Importantly, they also found that the drop shows no short-term structural effects on the eye, with only temporary changes in blood flow inside the retina. 

Ostrin’s latest research is published in the journal Eye and Vision. It adds to a growing body of vision research from David Berntsen, Golden-Golden Professor of Optometry at the University of Houston, who is co-leading a national $25 million NIH-funded clinical trial to delay the development of myopia in children by using the atropine drops. 

Low concentration atropine is widely prescribed to slow myopia progression in children, yet its short-term retinal and choroidal effects remain incompletely understood. Ostrin’s new study evaluated short-term effects of a range of low atropine concentrations on the length of the eye, the blood vessels in the retina and the thickness of the retina and choroid, which sits just behind the retina. These are important measurements because longer eye length is associated with myopia and as it gets longer, the retina and choroid are stretched.  

“These findings indicate that a single instillation of atropine does not alter axial length or retinal or choroidal thickness over 24 hours but may transiently affect superficial retinal perfusion in a time-dependent manner,” said Ostrin.  

In the double-masked, randomized study, twenty healthy adults received a single instillation of either a placebo or atropine in the right eye during five separate sessions. Researchers then checked the eye structure, thickness, and length in the central retina both one-hour and 24-hours later.  

“Characterizing these short-term effects is important for a better understanding of the physiological responses to atropine in clinical and research settings,” said Ostrin who previously published research results of a study investigating the short-term effects of a range of low-dose atropine concentrations on the pupils of young adults. In that study, she found similar results with a single drop of atropine inducing significant changes in the pupils. 

Together, the studies indicate that atropine induces early functional and vascular effects in the eye, in the absence of structural change.  

“By linking objective ocular responses with subjective visual experience, this work advances our understanding of how atropine works and supports more precise, evidence-based, and individualized approaches to myopia management,” said Ostrin. 

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Study: Egg consumption is associated with a lower risk of Alzheimer’s Disease

Compared to never eating eggs, eating at least five eggs per week can decrease risk of Alzheimer’s.

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Consumption of eggs is associated with a lower risk of being diagnosed with Alzheimer’s Disease for those 65 years and older, according to researchers at Loma Linda University Health

Eating one egg per day for at least five days a week reduces risk of Alzheimer’s by up to 27%, researchers found.

“Compared to never eating eggs, eating at least five eggs per week can decrease risk of Alzheimer’s,” said Joan Sabaté, MD, DrPH, a professor at Loma Linda University School of Public Health and the study’s principal investigator.

Even less frequent consumption of eggs significantly reduced the risk of Alzheimer’s. Researchers found that eating eggs 1 to 3 times per month had a 17% decrease in risk, while eating eggs 2 to 4 times per week had a 20% decrease in risk, Sabaté said.

The study, Egg intake and the incidence of Alzheimer’s disease in the Adventist Health Study-2 cohort linked with Medicare datawas published last week in the Journal of Nutrition.

Researchers said they embarked on the study because of a substantial knowledge gap in the relationship between modifiable dietary factors and risk of Alzheimer’s disease risk.

Eggs are known to be a source of key nutrients that support brain health. Sabaté said. Eggs provide choline, a precursor to acetylcholine and phosphatidylcholine, both of which are critical for memory and synaptic function, the study stated. Eggs also contain lutein and zeaxanthin—carotenoids that accumulate in brain tissue and are associated with improved cognitive performance and reduced oxidative stress. Eggs also contain key omega-3 fatty acids, and yolks are particularly rich in phospholipids, which constitute nearly 30% of total egg lipids and are essential for neurotransmitter receptor function.

Researchers said they studied the consumption of eggs in visible ways — such as eating eggs in various forms, like scrambled, fried, boiled, etc. — and hidden ways, such as eggs included in baked goods and packaged foods.

The cases of Alzheimer’s Disease in the Adventist Health Study 2 cohort were diagnosed by physicians, according to Medicare records, among the study population of 40,000 subjects. Eligibility was determined using the Medicare Master Beneficiary Summary Files. The average follow-up period was 15.3 years.

The team emphasized that moderate egg consumption should be  part of a balanced diet.

“Research supports eggs as part of a healthy diet,” said Jisoo Oh, DrPH, MPH, an associate professor of epidemiology at Loma Linda University School of Public Health and the study’s lead author. “Seventh-day Adventists do eat a healthier diet than the general public, and we want people to focus on overall health along with this knowledge about the benefit of eggs.”

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Telling people they might lose motivates more than telling them they might win, research shows

How managers choose to frame problems directly influences employees’ motivation to speak up at work. For managers, this is an insightful approach for building more open and collaborative teams.

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Athletes say they hate to lose more than they love to win. New research finds the same sentiment is shared in organizations.

A Virginia Tech researcher and his colleagues discovered that when managers frame work problems as a potential loss, employees are more likely to take action than when those problems are framed as potential gains. The research also revealed that when the potential loss impacts a larger group, employees are more likely to take action in the form of speaking up to a supervisor in hopes of finding a solution. The findings were recently published in the Journal of Applied Psychology.

For managers, this research suggests that framing work problems as potential losses can influence employees to speak up more.

“Employee voice occurs when suggestions are made to improve organizational functioning,” said Phil Thompson, associate professor in the Pamplin College of Business Department of Management. “From an organizational perspective, the positive outcomes of employee voice include improved performance, effectiveness, and workplace safety. From an employee level, speaking up is positively related to creativity, innovation, engagement, and ethical behavior.”

At its core, this research shows that how managers choose to frame problems directly influences employees’ motivation to speak up at work. For managers, this is an insightful approach for building more open and collaborative teams.

“When managers say, ‘If we don’t get this done, not only will you lose the $5,000 bonus, but everybody in this work group is going to lose a $5,000 bonus,’ it magnifies an employee’s motivation to act in a proactive way,” said Thompson. “This suggests that framing work problems as what will be collectively lost – compared to what can be individually lost – makes employees want to speak up more.”

Thompson was part of a research team led by Jeffery Thomas and Jonathan Booth from The London School of Economics and Mark Bolino from Oklahoma University. Together they analyzed responses from nearly 2,000 full-time employees, MBA students, and employee-supervisor pairs for their experience in situations where work problems were framed as either a gain or a loss. Across three different studies, framing something as a loss yielded employees to voice a work suggestion more.

For example, a manager dealing with a reputational crisis of their team, such as a product quality issue, can frame the problem in a way to spark helpful employee suggestions on how to resolve the issue. For example, instead of saying “if this product has great quality, our company will look really good” a manager saying “if this product is not up to quality standards, our reputation will be damaged” carries more weight for the team. When this reputational risk is shared by everyone, employees are more willing to step forward to help the problem.

In the first study, participants were asked to think about a problem at work that was significant for them. From there, they were randomly assigned to write about the potential losses or gains from that problem. They were also asked to indicate how likely they were to talk about these problems to their supervisor. Participants who reflected on their potential losses showed a 16 percent higher willingness to speak up compared to those who focused on the potential gains.

When it came to the MBA students, they read a fictional performance review scenario where a workplace problem was described. They then rated how willing they would be to speak up about that scenario if they were in the situation. One example suggested that the entire team might fall short of its goals if an issue was not addressed. This specific scenario yielded the most likelihood of speaking up 35 percent more than the scenario’s suggesting that only they would miss their goal, supporting the research’s findings that an employee is more likely to speak up when the loss impacts more people.

The third study looked at employee-supervisor pairings to understand how these relationships play out in the real world. Using pairings from across three industries, employees reported a workplace problem they encountered and their supervisor rated how often that employee spoke up on the job. While the first two studies involved hypothetical scenarios, this real-world evidence showed that employees were 8-10 times more likely to speak up when issues were framed as a potential collective loss compared with a potential collective gain. 

“This research is really geared toward managers so they can facilitate and understand how and why their employees will speak up,” said Thompson. “You can talk about the issue, but it always ends in terms of how we frame things.” 

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