for many decades where doctors and dietitians have urged people to limit their intake of high-fat foods. citing links to poor health outcomes. and some of the leading causes of death in the United States, such as diabetes, heart disease and cancer.
According to the Centers for Disease Control and Prevention Food ingredients high in saturated fat, such as red meat, are a risk factor for colon cancer. Diet is believed to have a strong influence on colorectal cancer risk. And changing eating habits may help reduce the cancer burden by 70%.
Other known epidemiological risk factors include family history. Inflammatory bowel disease, smoking, and type 2 diabetes
But of all the risk factors that increase colon cancer risk. Diet is one of the most easily controlled environmental and lifestyle factors. Just change people̵7;s behavior and eating habits. If we know the exact relationship
“There is epidemiological evidence linking obesity and tumor risk,” said Miyeko Mana, an assistant professor in the School of Life Sciences, “and in the gut, stem cells are the most prone to cancer. What is that? Well, diet is what feeds the cycle of obesity and colon cancer.”
Now, a new ASU study led by Mana and her team has shown in greater detail than ever that a high-fat diet can trigger molecular events that lead to colon and colon cancer. The study was published in the journal cell report.
Tales from the Basement
Because food is digested and moves into the intestines. They interact with intestinal stem cells (ISCs) located inside of the intestine. These ISCs live in the valleys of the regularly folded intestines called crypts.
ISCs are thought to be the gateways that coordinate intestinal tumor formation when adapted to a high-fat diet. and increase the risk of cancer. Inside ISCs are high-fat sensor molecules that detect and respond to high-fat diet levels in cells.
“We are pursuing a mechanism that may be necessary for stem cells to adapt to a high-fat diet. And that’s what we found in PPARs,” Mana said. The peroxisome proliferator (or PPAR)-activated receptor activates cellular programs that increase cancer risk. But the exact mechanism is unclear due to the different types of PPARs and the complexity of mimicking their role.
“There are 3 PPAR families named Delta, Alpha and Gamma. At first I thought only PPAR delta was involved. But to see if the gene is really responsible for the phenotype, you have to take it off.”
Mana’s team was able to explore and uncover the roles of each PPAR delta and alpha using mouse models that control intracellular activity. In her team’s study The rats were fed a high-fat diet or regular diet long term. and the activity of each PPAR was carefully monitored to study its effects on cancer risk.
in the amazing study They first removed the PPAR delta gene.
“But when we take it out of the intestines We still observe the phenotype. So we wonder if there might be another PPAR to compensate, and that’s what we think about both PPAR alpha (PPAR delta and PPAR alpha) seems to be necessary for This high-fat food phenotype within the stem cells.”
This was disappointing for Mana, as she immediately realized that developing a potential treatment to compensate for PPAR had become a much higher task.
“When you think about this treatment If you put a lot of fat in your diet and you want to reduce your risk of colon cancer. Targeting two different factors is more challenging if you are targeting just one factor.”
Look a little deeper below
To further tease out the genetic complexity, Mana turned her attention to the downstream of PPAR.
Through research studies and using new tools in the trade, they can gradually Tease details to the level of molecular sequencing from individual cells from different regions. of the small and large intestines mass spectrometry to quantify various metabolites and radioactively labeled isotopes of fuel sources to measure carbon flow.
Their first major clue came from metabolic analyzes. A high-fat diet found in isolated ISC crypt boosts fat metabolism. At the same time it reduces the breakdown of sugar.
“So we’re looking more downstream on what these two factors (PPARs) might be targeting, and that is the mitochondrial protein Cpt1a,” Mana said. to use LCFAs as part of a high-fat diet.”
And when they conducted the mouse knockout Cpt1a study, They found that they were able to stop tumor formation in its pathway. The loss of Cpt1a made both proliferation and spread of cryptic ISCs imperceptible.
“If you remove Cpt1a, you survive this high-fat diet phenotype in intestinal stem cells,” Mana said, “so you can reduce your risk of developing tumors at this point.”
new version coming out
Based on their data, Mana’s team was able to track the cancer’s development. From diet to tumor formation
First, fats are broken down into free fatty acids. The free fatty acids then activate sensors such as PPAR and turn on genes capable of breaking down fatty acids.
Next, excess free fatty acids are transported to the mitochondria. which can metabolize them by oxidation to provide more energy to feed the stem cells. This will multiply, grow and rebuild tissues in the intestines. But as the number of ISCs increases, there is a greater likelihood that mutations will occur—just through random mutations and the actual number of cells—leading to colon cancer.
“The idea is that this large cell cluster remains in the gut and accumulates the mutation. And that means they can be a source of mutated cells, leading to tumor transformation and initiation,” Mana said. “We think this is possible when there are conditions that expand your stem cell pool.”
Mana’s group also found that feeding a high-fat diet greatly accelerated mortality in this model. compared with the control conditions by accelerated tumorigenesis.
“The level of these fats you get from your diet affects your stem cells. It’s probably quite straightforward,” Mana said. But you can remove these PPARs, you can remove CPT1a and the intestines are fine.”
With new evidence from this study The hope is that one day they will apply their work to human colon cancer.
“These studies have all been in these mouse models to date,” Mana said. “One idea we started with was to understand the metabolic dependence of tumors that can occur in natural or pharmacological contexts. These metabolic programs are then targeted at tumor damage. but not normal tissue We’re working on high fat. Ultimately, the goal is to eliminate or prevent colorectal cancer in humans.”
Study explores how a high-fat diet affects colon cancer.
Miyeko D. Mana et al, Fatty acid-stimulated oxidation of a high-fat diet mediates intestinal inhibition and tumorigenesis. cell report (2021). doi: 10.1016/j.celrep.2021.109212
Provided by Arizona State University.
reference: Study showing a new link between a high-fat diet and colon cancer (2021, June 9). Retrieved June 10, 2021, from https://medicalxpress.com/news/2021-06-links. -high-fat-diets-colon.html
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