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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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Common drug class may increase risk of heart disease

The risk of cardiovascular disease increased in line with how much anticholinergic medication the participants used each year. Those with the highest exposure had a 71 per cent higher risk of a cardiovascular event than people who did not use anticholinergic medication at all.

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People who use drugs with anticholinergic effects, including certain antidepressants, drugs for urinary incontinence and common antihistamines, are at higher risk of developing cardiovascular disease.

This is shown in a study from Karolinska Institutet published in BMC Medicine.

Anticholinergic drugs reduce the effect of the neurotransmitter acetylcholine and are commonly prescribed to middle-aged and older people. This large group of drugs includes antihistamines used for allergic conditions, anxiety or insomnia, drugs for urinary incontinence, and certain antidepressants, where tricyclic antidepressants have a strong anticholinergic effect, whereas SSRIs have a weaker effect. A high cumulative use of these drugs, referred to as anticholinergic burden (see fact box), has previously been linked to impaired cognitive ability. 

May affect heart regulation 

The new study suggests that the drugs may also affect the parasympathetic nervous system and thereby the regulation of the cardiovascular system. The results show that it may be important to monitor the total drug burden in everyday clinical practice.

The study included more than 500,000 people in Stockholm, Sweden, who were 45 years of age or older and had no prior cardiovascular disease, except for hypertension, at the start of the study. The researchers followed the participants for up to 14 years and analysed how the use of anticholinergic drugs was associated with the development of cardiovascular disease.

“Many of these drugs are used by older people and by people with multiple medical conditions. We wanted to investigate whether the total exposure had any significance for the risk of developing cardiovascular disease over time,” says Nanbo Zhu, postdoctoral researcher at the Department of Neurobiology, Care Sciences and Society, Karolinska Institutet.

71 per cent higher cardiac risk

The study showed that the risk of cardiovascular disease increased in line with how much anticholinergic medication the participants used each year. Those with the highest exposure had a 71 per cent higher risk of a cardiovascular event than people who did not use anticholinergic medication at all. The association was seen for all types of cardiovascular disease but was particularly clear for heart failure and various forms of arrhythmia.

“Our results indicate that the cumulative drug burden can affect heart regulation, not only in the short term but also over the long term. This does not mean that the drugs should always be avoided, but that exposure should be monitored carefully,” says Hong Xu, assistant professor at the Department of Neurobiology, Care Sciences and Society.

The researchers point out that the study is observational, meaning it cannot establish a causal relationship. Other factors, such as underlying diseases, may also influence the associations.

The work was carried out within the Stockholm CREAtinine Measurements project in collaboration between several research groups at Karolinska Institutet and Region Stockholm. The study was funded by the Swedish Research Council, the Center for Innovative Medicine Foundation, and other foundations. Some researchers report assignments for the pharmaceutical industry, which are disclosed in the scientific publication.

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Mindfulness practices found to significantly reduce depression symptoms, especially for those with early-life adversity

Mindfulness interventions help by regulating our emotions better when different challenges come up. For someone who has experienced childhood neglect or abuse, mindfulness training can help us make sense of that and respond skillfully to this moment in time.

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A new study reveals that mindfulness practices may significantly reduce depression symptoms, particularly in people who have experienced early-life adversity, such as childhood abuse and neglect.

Led by Eric Loucks, professor of medicine, epidemiology, and of behavioral and social sciences and director of the Mindfulness Center at Brown, the study enrolled 201 participants, 101 of whom were randomized into the Mindfulness-Based Blood Pressure Reduction Program, while 100 were randomized into an enhanced usual care control, which included home blood-pressure monitors, physician access and health-education materials. Researchers also had a measure of participants’ early-life adversity, particularly their exposure to abuse or neglect.

Loucks and his team followed participants for six months to assess changes in blood pressure, health behaviors and mental health, finding that those in the mindfulness program showed significant improvements in their depression symptoms. Additionally, participants who experienced childhood neglect showed greater improvements in depression symptoms than those who had not. A similar, though less pronounced, trend was observed among people with a history of childhood abuse.

“In this program, that was primarily designed to lower blood pressure while addressing whole-person health, we also saw that mental well-being, particularly around depression symptoms, improved in participants that went through the program,” Loucks said. “The findings suggest that cultivating mindful self-regulation skills–such such as self-awareness, attention control and emotion regulation–may help interrupt maladaptive patterns shaped by past experiences.”

Over the last 15 years, Loucks has been studying social determinants of health such as early-life adversity and its impacts on cardiovascular health, body mass index and blood pressure. “I came to a point where I wanted to not just document it, but do something about it, and I wondered if mindfulness training might help,” he said. “I’d gone through a lot of mindfulness training myself outside of work and started to get trained up in mindfulness programs that are specific to health contexts.”

Loucks began to study the Mindfulness-Based Stress Reduction program, running it through two clinical trials that were funded by the NIH and finding that it reduced blood pressure in both trials. He also wanted to look at the intervention from a whole-person perspective.

“If we look at everyday folks out in the world, those that had exposure to early life adversity, like abuse and neglect, tend to have worse mental health and also worse cardiovascular health,” Loucks said. “Mindfulness interventions help by regulating our emotions better when different challenges come up. For someone who has experienced childhood neglect or abuse, mindfulness training can help us make sense of that and respond skillfully to this moment in time.” 

Loucks discussed this work during a keynote address at the U.S. DOHaD Society this year. “It felt like a coming-home moment to see that this intervention, originally developed to address psychosocial factors that influence health, had even stronger effects among people with early-life adversity, particularly on depression,” he said. “It’s been about a 15-year arc of research that culminated in these findings.”

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High-fiber diet linked to reduced risk of heart disease in night shift workers

A moderate intake of about 19 grams of fibre per day was linked to a lower risk for those who worked night shifts regularly. For those who worked night shifts sporadically, about 15 grams was enough. The current recommendation for adults is about 25 grams of dietary fibre per day.

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People who work at night have a higher risk of coronary artery disease, a type of heart disease. A new study suggests that a higher fibre intake in the diet may help reduce this risk. The study included over 220,000 adults in the UK and is published in the European Journal of Epidemiology.

The human body is built to sleep at night. This means that working during the night goes against this natural pattern, and can place additional strain on the body, including the heart. Previous research has linked night work to an increased risk of coronary artery disease. Since night work is often unavoidable, the researchers wanted to investigate whether certain dietary habits might have a protective effect.

More fibre associated with lower risk

The researchers used data from 220,000 adults in the UK Biobank (2006–2010) and divided the participants into three groups:

  • Day workers
  • Shift workers who worked night shifts sporadically
  • Regular night shift workers

The participants had completed a detailed questionnaire about their dietary habits. During a follow-up after about 12 years, it was found that night shift workers who consumed little fibre in their diet had a higher risk of coronary artery disease than those who consumed more fibre.

“A moderate intake of about 19 grams of fibre per day was linked to a lower risk for those who worked night shifts regularly. For those who worked night shifts sporadically, about 15 grams was enough. The current recommendation for adults is about 25 grams of dietary fibre per day,” says Diana Nôga, lead author and researcher at Uppsala University.

The researchers stress that the figures from the study are not official dietary recommendations. But they do show a pattern in this UK study: a higher dietary fibre intake was linked to a lower risk of heart disease among night shift workers.

“The link between fibre and a lower risk of heart disease is not just because those who eat more fibre generally have a healthier lifestyle. We know this because we adjusted for various lifestyle factors in the analysis. One possible explanation, supported by previous research, is that fibre in the diet can improve intestinal flora and also reduce lipids, which can be particularly good for the heart in people who work at night,” says Christian Benedict, senior author of the study and Professor of Pharmacology at Uppsala University.

Dietary fibre can support heart health

According to the researchers, an increased intake of fibre-rich foods such as whole grains, vegetables, fruit, legumes and lentils may be a simple way to improve heart health for night shift workers. However, this requires that you do not have any medical obstacles to doing this, such as chronic gastrointestinal diseases.

“Dietary changes should be seen as a complement to, not a substitute for, other heart health-promoting habits such as not smoking, remaining physically active, and getting enough sleep,” says Diana Nôga.

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