If your doctor tests your blood, and your total cholesterol is 240mg/dL, your doctor may tell you that you have “high” cholesterol. There are three components to our total cholesterol: High Density Lipoprotein (HDL) known as the “good” cholesterol, Low Density Lipoprotein (LDL) known as the “bad” cholesterol and triglycerides also known as fatty acids. Having high cholesterol causes no immediate symptoms, so unless you are tested regularly, you may not discover your cholesterol levels are high until you experience symptoms related to plaque buildup such as high blood pressure, chest pain, shortness of breath or even a serious event like a heart attack or stroke.
Most people can lower their cholesterol by getting more active, eating healthier food (more fruits and veggies; avoiding cholesterol-rich foods like cheese and fried foods), and losing weight. However, don’t be fooled! There are many very fit individuals with active lifestyles who have high cholesterol. This is because cholesterol levels can also be influenced by our genetics. If lifestyle changes just are not enough to lower cholesterol to a healthy level, a physician may recommend additional treatment including prescription drugs called “statins” that help lower cholesterol. Statins work by masquerading as an enzyme called HMG-CoA that controls cholesterol production in your liver and also helps your liver recognize and reabsorb LDL (2).
Still, drug companies are constantly searching for newer and more effective drugs. Some reasons for doing this (besides improving profits after patents expire) is because statins simply are not effective in some people and about 20% of people cannot tolerate the side effects of statins, which can include muscle weakness and memory loss. Academic researchers work hard to understand how our bodies process cholesterol and why some people have high cholesterol and others can eat all the pizza and cheese they want and never see a problem.
One protein/enzyme, known as PCSK9, has been particularly popular in recent years as a potential therapeutic target. PCSK9’s job is to block and trigger destruction of receptors in the liver that help absorb LDL, which is just the opposite of what the statin is doing. (Remember: your body is all about maintaining homeostasis, so it has mechanisms that will both increase and decrease bad cholesterol in an attempt to keep it in balance. Sometimes one drug or approach will be more effective than another since we are all unique individuals; even when it comes to our biochemistry!) An interesting story (3) was released earlier this spring about mutations present in the gene of the same name that encodes PCSK9. As stated in Nature, in 1999, researchers at the University of Texas-Southwestern launched a population-based study of 3500 Dallas residents and began collecting physical measurements that related to heart disease. About half of the participants in this study identified as Black (I assume the other half identified as White). The study also included a mix of males and females (Note: Before 1963, clinical trials generally only included White males largely because females were thought to be too complicated due to the fluctuations in hormonal cycles. Perhaps surprisingly, designing trials with participants of diverse race and gender, or focusing on anyone other than White males is a fairly modern concept.) The results of this study show why diversifying a sample population helps yield amazing information. Needless to say, studying only one race or gender is like only dumping half of the puzzle pieces out of the box and then wondering why you can’t put the puzzle together.Over the years, the data collected in the Dallas study were analyzed many different ways. Long story short, researchers identified a Black female in the study whose LDL measured at a mere 14mg/dL! It turns out that there are two nonsense mutations in the PCSK9 gene that appear to stop production of the PCSK9 protein resulting in a 40% reduction in blood LDL levels. In the Dallas study, only 2% of Black participants had one of the two mutations. The mutation exists in 3% of Whites, but does not completely block production of the PCSK9 protein, so the effects are not nearly as dramatic. The individual with startlingly low blood LDL just happens to have two copies of the mutated gene, so PCSK9 is effectively knocked-out. Thankfully, this woman has been open to being studied by science. Doctors have been somewhat surprised that she is perfectly healthy, given that balance in cholesterol levels is so important for normal physiology and health.
It took a few years for academic researchers to jump on the PCSK9 bandwagon, but it is now a popular target for therapeutic strategies to lower bad cholesterol. It is proving to be difficult to find a small molecule (i.e. drug in pill form) that will disrupt the protein’s action. A promising approach currently in clinical trials involves injecting an antibody into the skin (much like insulin) that binds to the protein to interfere with its action. Injectable antibodies as therapies tend to be very effective, but not as popular as pills because it is easier for a patient to take a pill than give themselves a shot. Antibody therapies are also relatively quite expensive. A very recent study (4) released promising results in a small clinical trial blocking the PCSK9 protein using a piece of RNA (DNA’s less advertised cousin) in a method known as RNA interference. This method is even less desirable than antibody therapy because the RNA must be injected into a vein. However, if you are one of those people that is at severe risk of heart disease or stroke because you just can’t get your cholesterol down, you might not care about the delivery method if it is the only thing that saves your life.
- “What Is Cholesterol? – NHLBI, NIH.” NIH Heart, Lung and Blood Institute. N.p., n.d. Web. 4 Oct. 2013. <http://www.nhlbi.nih.gov/health/health-topics/topics/hbc/>.
- Crosta, Peter. “What Are Statins? How Statins Work And The Side Effects Of Statins.” Medical News Today: Health News. N.p., 27 Sept. 2013. Web. 4 Oct. 2013. <http://www.medicalnewstoday.com/articles/8274.php>.
- Hall, Steven S.. “Genetics: A gene of rare effect : Nature News & Comment.” Nature Publishing Group : science journals, jobs, and information. N.p., 9 Apr. 2013. Web. 4 Oct. 2013. <http://www.nature.com/news/genetics-a-gene-of-rare-effect-1.12773>.
- Ledford, Heidi. “RNA-based cholesterol drug shows early promise : Nature News & Comment.” Nature Publishing Group : science journals, jobs, and information. N.p., 3 Oct. 2013. Web. 4 Oct. 2013. <http://www.nature.com/news/rna-based-cholesterol-drug-shows-early-promise-1.13873>.
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