Nav: Home

Bad cholesterol: 'Slim down' fat-carrying particles to reduce its spread

January 28, 2019

  • Enzyme DGAT1 controls how much fat is added to particles released by the liver to be delivered around the body
  • More fat makes bigger particles, which increase the presence of 'bad' cholesterol in blood
  • Inhibiting DGAT1 allowed scientists from University of Warwick to 'slim down' particles and load them with less fat
  • Opens potential to use changes in diet to produce the same effect
  • Could pave the way for new treatments for heart disease, strokes and diabetes


The enzyme that 'loads up' fat-carrying particles in the liver before they are transported around the body has been identified for the first time by scientists at the University of Warwick.

The discovery also reveals how to 'slim down' these particles to reduce the amount of the worst type of 'bad' cholesterol distributed throughout the body and could pave the way for new treatments to prevent heart disease and strokes.

A study published by Professor Victor Zammit from Warwick Medical School in the Journal of Lipid Research examined the effects of inhibiting the production of the enzyme diacylglycerol acyltransferase 1 (DGAT1). This enzyme is present in the liver and is associated with the production of Very Low-Density Lipoproteins (VLDL). These contain fat in the form of triglycerides choesterylesters, cholesterol, and are surrounded by proteins and charged lipids.

VLDL particles are the body's fat couriers, travelling all over the body through the bloodstream to deliver fat to other tissues. They carry out the normal physiological process that allows the liver (and intestine) to distribute fat throughout the body, but when depleted of triglycerides they become carriers of 'bad' cholesterol which they deposit in our arteries. The amount of fat the particles carry determines their size - and the larger they are, the more 'bad' the cholesterol in them becomes.

The Warwick team found that inhibiting DGAT1 specifically in the liver decreased the size of VLDL particles by nearly half and reduced their triglyceride content, demonstrating that DGAT1 plays a key role in 'loading up' VLDL with fat. The study was funded by the Medical Research Council

Professor Zammit said: "VLDL particles themselves are not harmful but when they are depleted of triglyceride after they offload it to other tissues, they become Low-Density Lipoprotein which are the carriers of 'bad' cholesterol. This is the cholesterol that is associated with heart disease as the LDL deposit it within the walls of arteries, resulting in arteriosclerosis which can result in blockage of the coronary arteries with an associated increased risk of heart attacks and strokes.

"Our studies show that, when DGAT1 is absent from the liver, the number of particles is not altered much but their size and triglyceride content is halved. We know that conditions that increase cardiometabolic risk (for example diabetes) are associated primarily with increased size of the secreted particles. Size of the particles is the more important parameter in determining that risk because it prolongs the time that the particles stay in the circulation, during which time they become more 'sticky' in relation to the vascular lining.

"Our findings identify the enzyme (DGAT1) as the key determinant of the content of triglycerides, and therefore the size, of VLDL particles."

The research follows detailed previous studies (funded by the British Heart Foundation and Diabetes UK) on the properties and distinctive distribution of this enzyme in liver cells. As well as helping in the fight against heart disease and stroke, an understanding the mechanism of changes in DGAT1 activity and cellular distribution will also benefit those with diabetes, which is characterised by secretion of large VLDL particles.

Professor Zammit adds: "The findings will be useful for the pharma industry to work on pharmacological strategies to control the activity of DGAT1 in the liver, particularly that fraction of it that determines VLDL size. Preliminary studies suggest that this is also modifiable by nutrients in the diet, such as by altering the carbohydrate/fat ratio or saturated/unsaturated fat ratio. Therefore, the present findings may provide the basis for dietary recommendations to facilitate the decrease of VLDL size, and its propensity to give rise to dangerous levels of particles containing the worst type of cholesterol.

"We now want to find the mechanism through which the DGAT1 activity and distribution can be controlled physiologically so that we can mimic these mechanisms pharmacologically, as well as determining how changes in diet can affect this mechanism."
-end-
* 'Hepatic VLDL secretion: DGAT1 determines particle size but not particle number, which can be supported entirely by DGAT2' published in Journal of Lipid Research, doi: 10.1194/jlr.M089300

Notes to editors:

For more information contact:

Peter Thorley
Media Relations Manager (Warwick Medical School and Department of Physics) | Press & Media Relations | University of Warwick
Email: peter.thorley@warwick.ac.uk | Tel: +44 (0)24 761 50868 | Mob: +44 (0) 7824 540863 |

University of Warwick

Related Heart Disease Articles:

Where you live could determine risk of heart attack, stroke or dying of heart disease
People living in parts of Ontario with better access to preventive health care had lower rates of cardiac events compared to residents of regions with less access, found a new study published in CMAJ (Canadian Medical Association Journal).
Older adults with heart disease can become more independent and heart healthy with physical activity
Improving physical function among older adults with heart disease helps heart health and even the oldest have a better quality of life and greater independence.
Dietary factors associated with substantial proportion of deaths from heart disease, stroke, and disease
Nearly half of all deaths due to heart disease, stroke, and type 2 diabetes in the US in 2012 were associated with suboptimal consumption of certain dietary factors, according to a study appearing in the March 7 issue of JAMA.
Certain heart fat associated with higher risk of heart disease in postmenopausal women
For the first time, researchers have pinpointed a type of heart fat, linked it to a risk factor for heart disease and shown that menopausal status and estrogen levels are critical modifying factors of its associated risk in women.
Maternal chronic disease linked to higher rates of congenital heart disease in babies
Pregnant women with congenital heart defects or type 2 diabetes have a higher risk of giving birth to babies with severe congenital heart disease and should be monitored closely in the prenatal period, according to a study published in CMAJ.
Novel heart valve replacement offers hope for thousands with rheumatic heart disease
A novel heart valve replacement method is revealed today that offers hope for the thousands of patients with rheumatic heart disease who need the procedure each year.
Younger heart attack survivors may face premature heart disease death
For patients age 50 and younger, the risk of premature death after a heart attack has dropped significantly, but their risk is still almost twice as high when compared to the general population, largely due to heart disease and other smoking-related diseases The risk of heart attack can be greatly reduced by quitting smoking, exercising and following a healthy diet.
Citrus fruits could help prevent obesity-related heart disease, liver disease, diabetes
Oranges and other citrus fruits are good for you -- they contain plenty of vitamins and substances, such as antioxidants, that can help keep you healthy.
Gallstone disease may increase heart disease risk
A history of gallstone disease was linked to a 23 percent increased risk of developing coronary heart disease.
Americans are getting heart-healthier: Coronary heart disease decreasing in the US
Coronary heart disease is one of the leading causes of death in the United States.

Related Heart Disease Reading:

Best Science Podcasts 2019

We have hand picked the best science podcasts for 2019. Sit back and enjoy new science podcasts updated daily from your favorite science news services and scientists.
Now Playing: TED Radio Hour

Jumpstarting Creativity
Our greatest breakthroughs and triumphs have one thing in common: creativity. But how do you ignite it? And how do you rekindle it? This hour, TED speakers explore ideas on jumpstarting creativity. Guests include economist Tim Harford, producer Helen Marriage, artificial intelligence researcher Steve Engels, and behavioral scientist Marily Oppezzo.
Now Playing: Science for the People

#524 The Human Network
What does a network of humans look like and how does it work? How does information spread? How do decisions and opinions spread? What gets distorted as it moves through the network and why? This week we dig into the ins and outs of human networks with Matthew Jackson, Professor of Economics at Stanford University and author of the book "The Human Network: How Your Social Position Determines Your Power, Beliefs, and Behaviours".