Lowering high cholesterol, particularly low-density lipoprotein (LDL) cholesterol, is one of the most important ways of preventing heart disease. In this article, we hope to discuss different attempts at lowering high cholesterol and further research opportunities to improve cardiovascular health.
How Cholesterol Is Absorbed Naturally
Cholesterol is a lipid used to make cell membranes, regulate metabolism, and produce vitamin D. When the body breaks down food, triglycerides move to the duodenum and have to be surrounded by bile salts created by the liver because they cannot dissolve in water. Then, these fatty-acid-bile-salt are broken down into smaller parts through emulsification. Lipases are enzymes made in the pancreas that then break down these triglycerides to free fatty acids, monoglycerides, diglycerides, and cholesterol, forming structures called micelles. Micelles are then broken down by enterocytes (cells lining the intestines). Cholesterol enters a special transporter called NPC1L1. Inside the enterocytes, the smooth endoplasmic reticulum packages the cholesterol into chylomicrons. Although these particles are too big to enter capillaries, chylomicrons enter through the lymph nodes and into the arteries to circulate throughout the body.
Chylomicrons have apoproteins attached on their surface, which bind to receptors on cells to release fatty acids to be used. Once used up, the chylomicrons are chylomicron remnants, and they travel into the liver to be reused. The phospholipids, triglycerides, and cholesterol form very low-density lipoprotein (VLDL) particles, which transport more phospholipids to cells and are returned as intermediate-density lipoprotein (IDL). From there, IDL may be cleared off in the liver or be converted to low-density lipoprotein (LDL) which primarily contains cholesterol and stays longer inside the bloodstream.
How Cholesterol is Broken Down Naturally
When there are too many LDL particles entering the blood cells, APO A1 is a protein produced by the liver which will bind to ABCA1, allowing for more cholesterol to exit the cell and attach to APO A1 to create a nascent HDL particle.
Another molecule called LCAT will then convert it into a mature HDL particle. Studies have long implied that an increase in HDL can decrease the amount of LDL cholesterol there is (Boden et al., 2000). However, another protein called CETP allows the HDL particle to give more cholesterol to VLDL particles to give them to cells. As a result, CETP inhibitors were thought to decrease LDL, but they have currently not shown to help cardiovascular health.
Why High Cholesterol Is Bad
Macrophages are immune cells that respond when there is too much oxidized LDL in the blood. They are attracted by cytokines sent by other cells absorbing the fat, and they will absorb the fat. According to Jin et al., macrophages will “shed” cholesterol from their cell membranes when they detect high levels of cholesterol (2018). However, if macrophages absorb too much fat, they clump together as foam cells in the blood vessels, resulting in plaques. These plaques are what make the vessel walls harden and decrease blood flow, resulting in heart disease.
Further Research
So how else can we aid the body in decreasing the amount of cholesterol circulating in the bloodstream?
Lowering LDL
Current Medications
Usually, statins are used to lower cholesterol. Statins are medications that reduce HMG-CoA reductase, which is an enzyme that produces cholesterol. Sensing that there is too little cholesterol being made, 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).
Trying to Decrease LDL Absorption
In the past, researchers have tried to decrease the amount of cholesterol in the system by decreasing LDL absorption from a protein called ABCA1, which is responsible for converting LDL particles into HDL particles. However, the drug Probucol was discontinued because it also resulted in decreasing high-density lipoproteins (HDL) levels. Since HDLs are important in breaking down LDLs in the liver, this method seems to be inefficient.
Preventing Plaque Formation
Detecting Foam Cells
It is necessary to target treatments for lowering cholesterol only when there are high cholesterol levels to begin with. So, we will need to detect the plaques first. Jin et al. designed an antibody (mAb 58B1) that can find “cholesterol microdomains” which are created by macrophages storing excess amounts of fat (Jin et al., 2018). Since this antibody does not react with normal LDL cholesterol, it may be an efficient antibody to detect plaque deposits.
Preventing Foam Cells From Forming
In another research experiment, Crossey et al. targeted the protein PCSK9, a molecule that inhibits macrophages from ingesting LDL proteins and allows more LDL cholesterol to flow. By preventing LDL from building up, they may prevent macrophages from collecting LDL proteins and forming plaques. However, it is unclear how LDL particles get absorbed if they are not absorbed by macrophages (2015). So, this treatment may be best if there are also more HDL particles getting produced by increasing the amount of APO1 molecules from the liver.
Increasing Cholesterol Metabolism
Liver X receptors (LXRs) are chemical structures regulating the transcription of genes that help with carbohydrate and lipid metabolism. Synthetic LXR agonists (proteins helping these receptors) have shown to increase cells’ metabolism and absorption. For example, decreasing the amounts of TO9 (TO901317) may help decrease fat deposition.
Another way that the body tries to decrease excess amounts of LDL cholesterol is through bile. However, in trying to increase the amount of bile, bile can build up as gallstones in the gallbladder, which can cause cholecystitis. One point of research might be upregulating the production of bile when the body senses that there are a lot of fatty acids to digest. One way that could happen is to upregulate the production of bile only when there is an increased amount of the antibodies present.
Limitations to Preventing Plaques
What happens if LDL is left unabsorbed? Can it just bypass the bloodstream and get filtered out? Moreover, it seems that macrophage buildup is mediated by oxidation, and not the presence of LDL (Linton et al., 2019). What would happen if there was a buildup of LDL cholesterol, would it get filtered out in the kidneys? Indeed, decreasing LDL-absorption leads to LDL staying inside the bloodstream, which only gets filtered out through the kidneys, increasing the rate of kidney disease (Haynes et al., 2014).
Prevention Research
So, if it is inevitable that LDL cholesterol will have to go somewhere once it enters the bloodstream, would it be possible to avoid this from happening completely? What if the body just “threw away” any excess cholesterol once it recognizes that it already has enough?
Avoiding the Problem Entirely by Not Digesting Fats
Another potential point of research is nanocellulose, where DeLoid et al. attempt to reduce digestion and absorption of ingested fat so it can pass through the body (2018). Since fatty acids are not able to be digested without using an enzyme called lipase, nanocellulose was used to “hide” triglycerides so that they were unable to be broken down and absorbed by the body, passing through the body to not enter the bloodstream.
Further Research
It is possible to measure cytokines and macrophage populations through spit (Theda et al., 2018). I would be interested in looking at the different amounts of the above receptors in a sample of spit (which will contain some amounts of macrophages). Would it be possible to tag certain types of cytokines responsible for macrophage clotting or foam cell formation?
Week 1 : Article
Week 2 : Literature Review
Week 3 : Research Proposal
Week 4 : Further Research
Week 5 - 6 : Presentations and Publications
References
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Brault M, Ray J, Gomez YH, Mantzoros CS, Daskalopoulou SS (June 2014). "Statin treatment and new-onset diabetes: a review of proposed mechanisms". Metabolism. 63 (6): 735–45. doi:10.1016/j.metabol.2014.02.014. PMID 24641882
Crossey E, Amar M., Sampson M., Peabody J., Schiller J.T., Chackerian B., Remaley A.
A cholesterol-lowering VLP vaccine that targets PCSK9. Vaccine. Volume 33, Issue 43,
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Haynes R , Lewis D , Emberson J , et al . Effects of lowering LDL cholesterol on progression of kidney disease. J Am Soc Nephrol 2014;25:1825–33.doi:10.1681/ASN.2013090965
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
Linton MRF, Yancey PG, Davies SS, et al. The Role of Lipids and Lipoproteins in Atherosclerosis. [Updated 2019 Jan 3]. In: Feingold KR, Anawalt B, Boyce A, et al., editors. Endotext [Internet]. South Dartmouth (MA): MDText.com, Inc.; 2000-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK343489/
Theda, C., Hwang, S. H., Czajko, A., Loke, Y. J., Leong, P., & Craig, J. M. (2018). Quantitation of the cellular content of saliva and buccal swab samples. Scientific reports, 8(1), 6944. https://doi.org/10.1038/s41598-018-25311-0
Wen Y, Leake DS. Low density lipoprotein undergoes oxidation within lysosomes in cells. Circ Res. 2007 May 11;100(9):1337-43. doi: 10.1161/CIRCRESAHA.107.151704. Epub 2007 Apr 19. PMID: 17446432.
