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The Role of Apolipoprotein C-III (apoC-III) in Atherosclerosis and Cardiovascular Disease

After we eat a meal, all that energy has to go somewhere. Body cells can use freely floating glucose sugar in the bloodstream, but fats are a bit trickier. Just like oil and water don’t mix, fats have trouble moving through the blood in our veins and arteries. They must be packaged inside special containers called lipoproteins in order to travel where they need to go. For fats that we eat, the fats (called triglycerides) are packaged into ultra-low-density chylomicrons by the digestive system. Our liver also processes and repackages fats. The liver makes very low-density lipoproteins (VLDL) out of triglycerides and ejects them into the bloodstream. VLDLs can then use the bloodstream to travel to fat cells or be converted into other forms of energy storage. The number of triglycerides in the bloodstream at once needs to be well regulated.

For adults, fasting triglyceride levels should be under 150 mg/dL. This number decreases to below 90 mg/dL for people under 19 years of age. Unfortunately, one in ten adults have high levels, called hypertriglyceridemia. When there are too many triglycerides, they can stick to the inside of the bloodstream. They can create and contribute to hard plaques, a condition called atherosclerosis. These put stress on the cardiovascular system and can lead to atherosclerotic cardiovascular disease (ASCVD). Very high triglycerides above 500 mg/dL is called severe hypertriglyceridemia. This can lead to even more problems, including chylomicronemia, pancreatitis, and death.

What contributes to high triglyceride levels? A lot, actually! A diet that is high in sugars and fats, excessive alcohol consumption, being overweight, and a sedentary lifestyle can contribute. Some conditions, such as diabetes, kidney and liver disease, and thyroid problems increase your chances. Anything that affects liver function is likely to change how the body processes fats and may increase triglycerides. This means some life-saving medications, including several cancer, hypertension, and HIV treatments may increase triglycerides. Some people have high or very high triglycerides – usually in the form of chylomicrons – even without these risk factors. This may be because of our genes.

One of the major genetic culprits for increased triglycerides is a gene called APOC-3. This gene codes for a protein of the same name: Apolipoprotein C-III (apoC-III). You can tell these apart because the gene is uppercase, italicized, and uses a (3), while the protein is mostly lowercase and uses roman numerals (III). The protein apoC-III can lead to some detrimental effects. Normal triglycerides bind to a different protein, apoC-II. This helps them get broken down in the bloodstream. ApoC-III binds to triglycerides in the same place as apoC-II but makes them less able to be processed. These triglycerides build up in the bloodstream and can cause atherosclerosis and ASCVD. Scientists also have evidence that apoC-III makes triglyceride-rich molecules stickier to the arteries. ApoC-III binds to chylomicrons very well, making these fats especially resistant to breaking down.

So why do we have apoC-III anyway? It turns out, not all of us do! Different people have different variations of the APOC-3 gene. Some people have a gene that produces excessive apoC-III protein, and a few have genes that produce none! People with defective APOC-3 genes seem to be just as healthy as everyone else. Maybe healthier, as their levels of triglycerides are very low, even after a fatty meal! Researchers consider a defective APOC-3 gene to be cardioprotective, meaning that it lowers the chances of heart disease.

Are there methods for us to lower the production of apoC-III and our triglyceride-rich chylomicrons? It looks possible. The liver produces more apoC-III in response to high levels of blood sugar and most fats, so lowering these may help. It decreases production of apoC-III when it encounters high levels of insulin or polyunsaturated fats (such as Omega-3 fatty acids). This may be helpful, but is bad news for those with type 2 diabetes. In these patients the bloodstream has extra glucose and lacks insulin.

Treating high triglycerides can be complicated. A diet low in alcohol, carbs, and fats but high in omega-3 fatty acids can help. Exercise and weight loss are often helpful. Doctors may also prescribe fibrates, nicotinic acid (niacin), or statins. Unfortunately, these medications may not work if you have excessive levels of apoC-III and high chylomicrons. A diet that is very low in fats – under 20 grams a day – has been the only option for some patients. New classes of medication may be helpful as well. Antisense oligonucleotides, gene therapy, and custom antibodies can be used to target the production of specific proteins. Antisense oligonucleotides, for instance, bind to APOC-3 mRNA in the cell, preventing it from creating apoC-III proteins. They do this with extreme specificity, targeting only the gene in question. They can also do this only in liver cells by being packaged in a special way. Drugs that target apoC-III production may be able to bring down otherwise stubbornly high triglycerides without too many side effects. A side effect of reading the ENCORE Research Group website is learning about these new medicines and when they may be available for you in a trial!

Sources:

Alves-Bezerra, M., & Cohen, D. E. (2017). Triglyceride metabolism in the liver. Comprehensive Physiology, 8(1), 1. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6376873/

Goldberg, R. B., & Chait, A. (2020). A comprehensive update on the chylomicronemia syndrome. Frontiers in endocrinology, 11, 593931. https://doi.org/10.3389/fendo.2020.593931

National Institute of Health, National Heart, Lung, and Blood Institute. (April 7, 2022). High blood triglycerides. U.S. Department of Health and Human Services. https://www.nhlbi.nih.gov/health/high-blood-triglycerides

Rahmany, S., & Jialal, I. (July 18, 2022). Biochemistry, Chylomicron. https://www.ncbi.nlm.nih.gov/books/NBK545157/

Taskinen, M. R., Packard, C. J., & Borén, J. (2019). Emerging evidence that ApoC-III inhibitors provide novel options to reduce the residual CVD. Current atherosclerosis reports, 21(8), 1-10. https://doi.org/10.1007/s11883-019-0791-9