Recently, I learned that scientists have been developing a gene therapy that could lower cholesterol for people with genetically high cholesterol levels (Nissen et al., 2022). And immediately, I thought: no way, because cholesterol has been notoriously one of the most important factors contributing to heart disease.
Looking more deeply, though, there’s still a lot of research to be done. Primarily, this gene therapy targets only one type of molecule, whereas there is an entire class of molecules that can contain cholesterol. So, what does it mean to have high cholesterol and how can we research more about it to improve heart health?
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Welcome to Teens In Health’s podcast for our 2022 Summer Researchathon, a free, six-day event where high schoolers will research topics in molecular biology and pathology. My name is Michelle To, and if you’re interested in molecular interactions contributing to cardiovascular disease, here’s a sneak peak on just one possible topic that you could be researching over this summer.
So first, what is cholesterol, and where does it come from? While you may have heard that there are two types of cholesterol, one “bad” cholesterol and one “good” cholesterol, cholesterol is just a lipid, or fat, that is necessary in making cell membranes, regulating metabolism, and producing vitamin D in our bodies.
And while I always grew up hearing that high cholesterol was determined by the kinds of food we ate, like egg yolks or meat, when we talk about “bad” cholesterol, we are actually talking about the excess cholesterol that remains in our blood, which is predominantly found in low-density lipoproteins, or LDLs.
Normally, lipoproteins are able to transport cells the necessary amount of cholesterol they need, and then they return to the liver to be broken down and reused. However, LDLs can last in the bloodstream for a very long time without returning to the liver. When an LDL lasts for too long in the bloodstream without being used up, it can become oxidized, which causes an immune reaction. Macrophages may try to absorb the oxidized LDL to prevent further oxidation, but these immune cells can clump together in blood vessels, forming plaques that can restrict blood flow and lead to heart disease. So if the problem is that LDL particles are leaving the bloodstream too slowly, how can we speed up their degradation?
Currently, most people with high cholesterol take statins, which are medications that inhibit an enzyme that produces lipoproteins called HMG-CoA reductase. If there are too few lipoproteins being circulated, liver cells (which use cholesterol to create vitamin D) automatically compensate by drawing cholesterol from the body. The problem with statins is that they inhibit HMG-CoA reductase from also producing other chemicals important for muscle function and sugar regulation (Brault et al., 2014).
As it turns out, we can learn more about further research by taking a look at how our liver already tries to do this.
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When a cell senses that it has too much cholesterol, it will activate an apolipoprotein on the surface of the LDL called APO A1, which converts the low-density lipoprotein to a high-density lipoprotein, or HDL, that gets carried back to the liver. This is why we normally call HDL cholesterol “good cholesterol” because it is cholesterol being carried away from cells and into the liver to be broken down.
So why not just increase the amount of HDL in the bloodstream and decrease the amount of LDL?
But the relationship between HDL and LDL cholesterol might actually be a little more complicated and exciting. For example, although doctors often suggest eating more foods rich in HDL cholesterol, the molecular pathways of how the body converts the food we eat into cholesterol could still be further explored.
Additionally, in trying to increase the amount of LDL cholesterol being broken down by the body, the drug Probucol also decreased the amount of HDL cholesterol being produced by the body, which ultimately resulted in its discontinuation but makes it an interesting case to study. Other therapies are now targeting molecules like PCSK9 and liver X receptors. And what if we could personalize treatment so that we could increase LDL breakdown when necessary? I've written an article on Teens In Health’s website about lipid and lipoprotein processing, but it opens up the floor for more questions to be explored.
[Interlude]
As part of Teens In Health’s 2022 Researchathon, our goal is to share our ideas so that you can share yours as well. Are you interested in cardiovascular health research or research in general? This summer, you could join our Saturday research sprints and explore your own research question along with others. For more information, please visit our website, and contribute your own research to our community.
My name is Michelle, and I hope you keep asking questions! Thanks for listening!
References
Hu, F.B., et al., Dietary fat intake and the risk of coronary heart disease in women. N Engl J Med, 1997. 337(21): p. 1491-9.
Jin, X., Dimitriadis, E. K., Liu, Y., Combs, C. A., Chang, J., Varsano, N., Stempinski, E., Flores, R., Jackson, S. N., Muller, L., Woods, A. S., Addadi, L., & Kruth, H. S. (2018). Macrophages Shed Excess Cholesterol in Unique Extracellular Structures Containing Cholesterol Microdomains. Arteriosclerosis, thrombosis, and vascular biology, 38(7), 1504–1518. https://doi.org/10.1161/ATVBAHA.118.311269
Kratz, M., Dietary cholesterol, atherosclerosis and coronary heart disease. Handb Exp Pharmacol, 2005(170): p. 195-213.
Nissen SE, Wolski K, Balog C, et al. Single Ascending Dose Study of a Short Interfering RNA Targeting Lipoprotein(a) Production in Individuals With Elevated Plasma Lipoprotein(a) Levels. JAMA. 2022;327(17):1679–1687. doi:10.1001/jama.2022.5050
