The Power of Triglyceride Research

I have a big box of random, outdated, single-purpose cables with clunky brick-sized power adapters that plug into a now-broken laptop, a bubble machine, an inflatable pumpkin, or… who even knows? What’s with all of those bricks, anyway, and why did so many devices come with their own unique plug? The answer, of course, is to stop us from being dummies and putting the wrong amount of electricity in the wrong device. The power bricks reduce the high-voltage power from the wall into a lower voltage, just right for the device to handle, because too much energy in the wrong place is a recipe for disaster.

This sentiment is true inside the body as well. A major energy source for muscles and the heart is free fatty acids (FFAs).^[1] Having energy delivered to the heart and muscles is great, but the body spends a lot of effort making sure the right amount of energy is delivered to the right place. Having random packets of energy flying free is like having a downed power line: dangerous. In the body, extra free fatty acids are packaged into storage units called triglycerides, which contain three (tri-) free fatty acids attached to a glycerol backbone.^[1]

Triglycerides are needed to live, but too many - especially in the wrong place - are dangerous. The prefix hyper- means “over” or “above” in Greek, and the suffix -emia means “presence in blood,” so high levels of triglycerides in the blood are called hypertriglyceridemia. This condition is fairly common, affecting around 10% of adults, and is associated with increased atherosclerotic heart disease and pancreatitis.^[2,3 Many people with hypertriglyceridemia have genetic risks, though environmental and lifestyle risk usually have a larger impact on triglyceride levels.^[4] Other risks for developing hypertriglyceridemia include:

• Lifestyle risks
  • High saturated- and trans-fat diet
  • High-sugar diet
  • Alcohol consumption
• Associated diseases
  • Metabolic syndrome
  • Obesity
  • Diabetes
  • Lupus
  • Kidney disease
• Certain medications
  • Steroids
  • Antivirals
  • Antipsychotics
• Pregnancy

Let’s quickly zip through how the body deals with triglycerides. As stated above, triglycerides are made of free fatty acids. Fats (like oil) don’t mix with water, and can’t easily travel through our water-based blood. Despite this, our body needs to deliver triglycerides to the muscles and heart cells, so they are further packaged with special proteins and other structural materials to make large, relatively safe delivery power bricks (actually, spheres). These spheres are called lipoproteins, lipo- meaning “lipid” or “fat” and protein meaning exactly what it sounds like. Triglyceride-rich lipoproteins are produced in the intestines and the liver, pack a lot of triglycerides into a water-friendly package, and deliver triglycerides to power the body.^[1,3,4] The amount of lipoproteins floating in the blood is kept in balance by what we eat, what the liver produces, and what is broken down.^[1,3,4] Lipoprotein recycling depends on many enzymes, including a critical one called lipoprotein lipase (LPL), which is in turn inhibited by angiopoietin-like 3 (meaning high levels of angiopoietin-like 3 increases the amount of triglyceride-rich lipoproteins in the blood).^[1] The pathway much more complex, but the upshot is that genetics can affect many parts of this pathway, decreasing the action of LPL, increasing the amounts of angiopoietin-like 3, or affecting parts of the lipoproteins themselves - any of which can contribute to hypertriglyceridemia.^[3,5]

So what can be done? Just like you should unplug electronics when they start sparking, the first step is to cut excess calorie intake - especially those that raise triglycerides. This means lowering fats (especially saturated fats), sugars/carbohydrates, and alcohol, which are turned into triglycerides.^[2] Even though triglycerides are made of fat, cutting sugar and alcohol may have the greatest impact on triglyceride levels. Adding fiber, omega-3 fatty acids, and aerobic exercise can help reduce triglycerides as well.^[2] Medical solutions include many general cholesterol-lowering medications like fibrates and statins, and some less mainstream medications like PCSK9 inhibitors and ezetimibe.^[1,2] Many people have success with these medications, but several act on the same systems in the body and have overlapping steps. This means that when one medication (e.g., statins) fails to lower triglycerides to safe levels, others like fibrates may also fail.^[2] Because of this, clinical trials continue to look for new pathways to power down hypertriglyceridemia. Early phase 1 and phase 2 studies (along with genetic evidence) have shown promise for a new class of investigational medications targeting angiopoietin-like 3.^[1,6] The hope is that this new investigational class, if it proves successful, will help lower angiopoietin-like 3, raise levels of LPL, lower triglyceride levels in the body, and reduce the risk of heart and pancreatic disease.^[6] Clinical research like this is our most powerful way to vet new medications, and is only possible because of the energy put in by amazing volunteers!

Creative Director Benton Lowey-Ball, MWC, BS, BFA

References:

[1] Reeskamp LF, Tromp TR, Stroes ES. The next generation of triglyceride-lowering drugs: will reducing apolipoprotein C-III or angiopoietin like protein 3 reduce cardiovascular disease?. Current opinion in lipidology. 2020 Jun 1;31(3):140-6. https://doi.org/10.1097/MOL.0000000000000679

[2] Laufs U, Parhofer KG, Ginsberg HN, Hegele RA. Clinical review on triglycerides. European heart journal. 2020 Jan 1;41(1):99-109c. https://doi.org/10.1093/eurheartj/ehz785

[3] Mohamed F, Mansfield BS, Raal FJ. ANGPTL3 as a drug target in hyperlipidemia and atherosclerosis. Current Atherosclerosis Reports. 2022 Dec;24(12):959-67. https://doi.org/10.1007/s11883-022-01071-1

[4] Ward NC, Chan DC, Watts GF. A tale of two new targets for hypertriglyceridaemia: which choice of therapy?. BioDrugs. 2022 Mar 14;36(2):121. https://doi.org/10.1007/s40259-022-00520-2

[5] Robciuc MR, Maranghi M, Lahikainen A, Rader D, Bensadoun A, Öörni K, Metso J, Minicocci I, Ciociola E, Ceci F, Montali A. Angptl3 deficiency is associated with increased insulin sensitivity, lipoprotein lipase activity, and decreased serum free fatty acids. Arteriosclerosis, thrombosis, and vascular biology. 2013 Jul;33(7):1706-13. https://doi.org/10.1161/ATVBAHA.113.301397

[6] Reeskamp, L. F., Tromp, T. R., Huijgen, R., Stroes, E. S., Hovingh, G. K., & Grefhorst, A. (2020). Statin therapy reduces plasma angiopoietin-like 3 (ANGPTL3) concentrations in hypercholesterolemic patients via reduced liver X receptor (LXR) activation. Atherosclerosis, 315, 68-75. https://doi.org/10.1016/j.atherosclerosis.2020.11.013

Reference Style changed from APA to AMA January, 2026