Findings Suggest Cholesterol Plays A Surprising Role In Pancreatic Cancer
Igor Astsaturov, MD, PhDOncologyLive
Although a majority of pancreatic cancer cells are highly dependent on endogenous biosynthesis of cholesterol, new research from investigators at Fox Chase Cancer Center has demonstrated that some more aggressive pancreatic cancers are completely independent of this process.
Although a majority of pancreatic cancer cells are highly dependent on endogenous biosynthesis of cholesterol, new research from investigators at Fox Chase Cancer Center has demonstrated that some more aggressive pancreatic cancers are completely independent of this process.
Disruption of cholesterol biosynthesis by Nsdhl knockout or treatment with statins transforms glandular pancreatic carcinomas in mice to the more aggressive basal subtype via the activation of SREBP1. When SREBP1 is cleaved and goes to the nucleus, this induces Tgfb1 expression, autocrine TGF-ßSMAD2/3 signaling, and epithelial-mesenchymal transition .
A recent multifaceted investigation by a group of scientists at Fox Chase and collaborators across the United States proved this finding and published the data in Cholesterol Pathway Inhibition Induces TGF- Signaling to Promote Basal Differentiation in Pancreatic Cancer, which appeared in the October 2020 issue of the journal Cancer Cell.1
Articlecholesterol Pathway Inhibition Induces Tgf
Knockout of Nsdhl switches pancreatic carcinoma from glandular to basal
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Statins or Nsdhl knockout activates SREBP1-dependent Tgfb1 expression and EMT
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PDACs in patients receiving statins have enhanced mesenchymal features
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LDL cholesterol in vitro or in patients antagonizes SREBP1 and autocrine TGF-
Involvement Of Ldl And Ox
- 1Division of Stem Cell Regulation and Application, School of Pharmacy, Hunan University of Chinese Medicine, Changsha, China
- 2Department of Urology, The First Hospital of Hunan University of Chinese Medicine, Changsha, China
- 3Institutional Key Laboratory of Vascular Biology and Translational Medicine in Hunan Province, Hunan University of Chinese Medicine, Changsha, China
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Binary Logistic Regression Analysis
Results of binary logistic regression analysis on the correlations between all indicators and the risk of CP showed that after gender, age, smoking, drinking, and BMI were adjusted, GLU and TC may be risk factors for CP and P value is 0.003 and 0.009, respectively and odds ratio value is 5.052 and 1.074, respectively and HDL-c may be a CP protective factor
Navigating The Cholesterol Pathway
Pancreatic ductal adenocarcinoma is poised to become the second-leading cause of cancer death in the United States by 2030. The median survival for patients with basal PDAC is much lower than that of the classical subtype , according to data from the COMPASS study .2
There are 2 major types of pancreatic cancer cells: classic, or glandular, and the more aggressive and treatment-resistant basal. Defined on the basis of transcriptional profiling, classic pancreatic cancer cells tend to grow in clusters and maintain features of epithelial differentiation. The basal variant features cancer cells that look like fibroblasts and are notoriously resistant to chemotherapy, resulting in far shorter life expectancies for patients .
To understand the metabolic dependencies of pancreatic cancer, we initially hypothesized that, by blocking biosynthesis of cholesterol in pancreatic cancer cells, we could suppress tumor development. We took advantage of a genetic mouse model in which we could turn off one of the cholesterol biosynthetic genes, Nsdhl. This protection happened in mice, in which cancer cells retained a single copy of the tumor-suppressor Trp53 gene. However, when the Trp53 gene was completely removed, the protection was lost and, surprisingly, the pancreatic cancer switched from classic to the basal subtype.
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Dangers Of Low Triglycerides
Low triglyceride levels are generally not dangerous. In fact, research supports the idea that low triglyceride levels can offer certain health benefits.
In one 2014 study, researchers found that lower non-fasting triglyceride levels were associated with a reduction in all-cause mortality in almost 14,000 study participants.
Another smaller 2017 study found that low triglyceride levels were linked to improved brain function in older adults without dementia.
However, incredibly low triglyceride levels may be linked to other conditions, as mentioned above. Some of these conditions in and of themselves may be dangerous, so it becomes important to treat the underlying condition thats causing low triglycerides.
Pancreatic Triglyceride Lipase Mediates Lipotoxic Systemic Inflammation
2Department of Laboratory Medicine and Pathology, Mayo Clinic, Scottsdale, Arizona, USA.
3Department of Pathology, and
4Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
5Department of Medicine, The Ohio State University College of Medicine, Columbus, Ohio, USA.
6Department of Pediatrics, Washington University in St. Louis, St. Louis, Missouri, USA.
Address correspondence to: Vijay P. Singh, Division of Gastroenterology and Hepatology, Mayo Clinic, 13400 East Shea Boulevard, Scottsdale, Arizona 85259, USA. Phone: 480.301.4286 Email: .
CDO and BK are cofirst authors.
Find articles byde Oliveira, C.in: |PubMed |
1Department of Medicine, and
2Department of Laboratory Medicine and Pathology, Mayo Clinic, Scottsdale, Arizona, USA.
3Department of Pathology, and
4Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
5Department of Medicine, The Ohio State University College of Medicine, Columbus, Ohio, USA.
6Department of Pediatrics, Washington University in St. Louis, St. Louis, Missouri, USA.
Address correspondence to: Vijay P. Singh, Division of Gastroenterology and Hepatology, Mayo Clinic, 13400 East Shea Boulevard, Scottsdale, Arizona 85259, USA. Phone: 480.301.4286 Email: .
CDO and BK are cofirst authors.
Find articles byKhatua, B.in:JCI |PubMed ||
1Department of Medicine, and
2Department of Laboratory Medicine and Pathology, Mayo Clinic, Scottsdale, Arizona, USA.
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Signs And Symptoms Of Pancreatic Cancer
Early pancreatic cancers often do not cause any signs or symptoms. By the time they do cause symptoms, they have often grown very large or already spread outside the pancreas.
Having one or more of the symptoms below does not mean you have pancreatic cancer. In fact, many of these symptoms are more likely to be caused by other conditions. Still, if you have any of these symptoms, its important to have them checked by a doctor so that the cause can be found and treated, if needed.
Low Levels Are Usually Protective
It is well known that high triglycerides are dangerous, but little is known about the influence of low levels on health. Studies suggest that in healthy people, low triglyceride levels are beneficial. Low triglycerides are also good for people with diabetes and might also be protective against heart attacks .
One study even suggests that the lower a persons triglycerides are, the less likely they will be to die from any cause. In this study, almost 14k people were followed for 24 years. The scientist found that levels below 89 mg/dL thats almost twice lower than the borderline-normal value of 150 mg/dL were associated with a 41% lower risk of dying than high levels
So can your levels ever be too low to do any harm?
We still dont have any definitive answers, but we can look for some clues.
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Treatments For High Triglyceride Levels
If you have high triglycerides, your doctor’s treatment should include healthy eating and exercise. Avoiding processed and sugary foods is paramount these dietary changes alone can have a tremendous impact on your triglyceride levels. Your doctor may also recommend taking omega 3 fatty acid supplements.
Begin today. Talk to your doctor or other health care provider about exactly what you need to do to start living a healthy lifestyle to lower triglycerides, help prevent a heart attack or stroke, avoid or manage diabetes, and reduce your chances of developing liver disease and pancreatitis.
What Is Considered Low Triglycerides
There isnt an official cutoff for low triglycerides. Most labs will consider any value below 150 mg/dL normal and values below 90 mg/dL as optimal.
If you are healthy and your values are lower than normal, you probably have nothing to worry about on the contrary.
But based on the studies above, in certain conditions, levels that are 50-70% lower than the average healthy persons might signal a more serious course of disease or higher levels of inflammation .
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Comparison Of Gender Age Smoking Drinking And Bmi Conditions Between The Cp And Nc Groups
There were 48 cases in the CP group, 27 males and 21 females the mean age was years there were 18 smokers and 16 drinkers and the mean BMI was kg/m2. There were 40 cases in the NC group, 20 males and 20 females the mean age was years there were 11 smokers and 8 drinkers and the mean BMI was kg/m2. The differences in gender, age, smoking, drinking, and BMI between these 2 groups all lacked statistical significance and had comparability .
High Triglycerides Tied To Pancreatitis Risk
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People are often advised to keep levels of triglycerides, a type of blood fat, in check to lower the risk of a heart attack. But high triglyceride levels may be linked to another problem as well: acute pancreatitis, a sudden and potentially fatal inflammation of the pancreas.
Danish researchers tracked 116,550 men and women over seven years. The risk for acute pancreatitis increased sharply as triglyceride levels rose. At 177 to 265 milligrams per deciliter, the risk increased by 130 percent at levels above 443, the risk increased by 770 percent. The associations remained after controlling for sex, age, alcohol intake, smoking, body mass index and other variables. The findings appeared in JAMA Internal Medicine.
Triglyceride levels below 150 are generally considered normal in terms of heart health in earlier studies, levels above 1,000 were considered to be a risk factor for pancreatitis.
The lead author, Dr. Borge G. Nordestgaard, a clinical professor at the University of Copenhagen, said that the absolute risk of acute pancreatitis is still small for most people.
I would be more worried about the risk of heart attack, he said, which is higher at the same levels of triglycerides. But patients should be concerned about both diseases if they have high triglyceride readings.
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What To Expect When Hospitalized With Pancreatitis From High Triglycerides
When you visit the ER with abdominal pain, the level of lipase in your blood will alert the doctor about the possibility of acute pancreatitis. This blood test is done in most patients who visit the ER with abdominal pain. Lipase is one of the enzymes made by the pancreas. A high lipase blood level means that the pancreas is damaged, and enzymes are spilling out into the blood. The higher the level of lipase, the worse the pancreatitis.
When there are no other obvious signs of pancreatitis, your doctor will order a lipid panel. If your lipid panel shows triglyceride levels of more than 1000mg/dl, you will be diagnosed with pancreatitis from high cholesterol.
Once diagnosed, you can expect the following treatment in the hospital:
As your pain improves, you can start to think about going home. You need to meet this criteria to be able to go home after being hospitalized with pancreatitis from high triglycerides:
Parameters Associated With Nafld
Table I demonstrates the patient characteristics. Age and HDL were significantly lower in patients with NAFLD compared to those without NAFLD . ALP, AST, ALT, -GTP, LDL, TG, BG and HbA1c were significantly higher in patients with NAFLD compared to those without NAFLD . Table II demonstrates the logistic regression analysis. TG was the parameter most significantly associated with NAFLD . With the parameters in Table II, the logistic curve was illustrated as an equation: ln = 3.8081 – 0.0104 × HDL + 0.0038 × LDL + 0.0087 × TG + 0.0081 × BG + 0.2626 × HbA1c . P represents the possibility of NAFLD.
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Triglycerides And Blood Sugar
Having high triglycerides could be a sign that youâre becoming insulin-resistant, which means your body isnât using insulin properly.
When insulin doesnât do its job, glucose can’t get into your cells. That raises your blood sugar levels, which can lead to pre-diabetes and, eventually, type 2 diabetes.
Having diabetes makes you much more likely to have a heart attack and other heart problems, in addition to the risk from your high triglycerides.
Untreated diabetes is a major health threat. To manage it well, you may need to track everything you eat, test your blood sugar, exercise, lose extra weight, take medication as directed, and keep up with your medical appointments.
Many people don’t know that they have diabetes. Your doctor should check on whether you do, and if so, help you get both your diabetes and your triglycerides under control.
Triglycerides Too High And Pancreatitis Risk Connection
Both cholesterol and triglycerides are fats in the blood that are very important to the body. They are responsible for many physiological processes. Cholesterol for instance, is useful in cell formation as well as the production of some hormones. It can come from foods that are eaten, however the body produces it as well . Triglycerides are the result of the breakdown of ingested fats. They are used by the body for energy and also used for its storage. While both of these elements are important to the body, having levels of cholesterol and triglycerides too high can create long term health complications like heart disease. But, there are other health conditions associated with having high triglycerides.
A normal triglycerides level is typically one that falls below 151 mg / dL. Anyone with levels below this is considered to have safe levels of triglycerides. Above this, risk of health complications grows along with the level of triglyceride elevation. Many times, achieving a normal triglycerides level is attainable with diet and exercise. Both limiting the intake of foods that can increase triglycerides levels as well as increasing physical activity can help reduce the presence of the blood fats.
References:
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Low Triglycerides May Be Serious
A finding of low triglycerides can be associated with its own range of adverse effects resulting in various health complications. Recent studies have found that low triglyceride levels combined with old age and a high class of NYHA heart failure can increase the likelihood of a cardiac problem and even stroke. This emphasizes that importance of having an overall balance within the body, as high triglycerides have been known for leading the development of fatal cardiac and stroke issues as well.
Low levels of triglycerides also impact other processes in the body such as the absorption of fat-soluble vitamins A, D, E, and K. These vitamins are involved in everything from the recycling of calcium to the production of beneficial blood clots.
Insulin resistance, a hallmark of type 2 diabetes, can be a consequence of having low triglyceride levels. This occurs when an increased metabolic rate can clear insulin from your system, along with triglycerides, at a faster rate. This can cause the glucose in the system to stick around longer going underutilized and pronging exposure to cells increasing their resistance to insulin.
Gene May Predict The Development Of Pancreatic Cancer
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What Are The Symptoms Of Pancreatitis From High Triglycerides
Symptoms of pancreatitis from high triglycerides are usually similar to but more severe than symptoms of pancreatitis from other causes. The higher the triglyceride levels, the more severe the symptoms.
Here are 3 common symptoms:
Abdominal pain from pancreatitis due to high triglycerides is usually felt in the mid-upper belly. The pain is sudden and worsens quickly. It spreads out in both directions like a thick belt. Pain may also radiate to your back. You usually have nausea and vomiting with the pain.
How Do Triglycerides Cause Pancreatitis
The product of fats breaking down, called free fatty acids, are thought to be very toxic to the pancreas, which makes digestive juices. These digestive juices break down fats, proteins, and carbohydrates in your food. Inside the pancreas, fats get broken down into fatty acid. Fatty acid damages the pancreas, and digestive enzymes leak out. These corrosive enzymes cause inflammation of the surrounding tissue, and you get severe pain associated with acute pancreatitis.
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Gallbladder Or Liver Enlargement
If the cancer blocks the bile duct, bile can build up in the gallbladder, making it larger. Sometimes a doctor can feel this during a physical exam. It can also be seen on imaging tests.
Pancreatic cancer can also sometimes enlarge the liver, especially if the cancer has spread there. The doctor might be able to feel the edge of the liver below the right ribcage on an exam, or the large liver might be seen on imaging tests.