Introduction

Cholesterol. We have heard of it basically everywhere. It is a constituent of eggs we consume regularly but we mostly hear of it in relation to disease. Too much cholesterol is bad for the heart is what I was told while growing up. Not false in any way but it took being a biochemistry major in the university to really understand how cholesterol really kills you potentially. The fun part was finding out there were the good cholesterol and the bad cholesterol.

So not all cholesterol kills? Impressive, I must say. In the course of my time in college, I got to know a lot about the metabolism of biomolecules. Lipid metabolism is just one of those areas. Well, since I like to take an argumentative approach to blogging these days. I will like you to once more be the judge of what I am about to present before you. Apolipoproteins or Cholesterol: Who Should Really Take The Blame in Coronary Heart Disease ?

A Discussion as Usual.

Cholesterol, a compound lipid, is a lipid that acts like a precursor to a whole lot of functional lipids. Cholesterol is formed via the mevalonate pathway and has acetyl CoA as its first major precursor. It is essential to know that when fatty acids (like palmitic acid) are broken down, we have acetyl coA (usually many molecules of acetyl coA). This goes through special pathways that ultimately lead to the production of ATP (the energy currency of the cell). This acetyl coA, however, can be utilized in the production of cholesterol. Fatty foods are mostly made up of triglycerides (which are made up of three fatty acid molecules attached to a glycerol backbone, I will spare you the technicality).

So what this implies is that, your fat-based diets can be harnessed by the body in producing cholesterol so there is a direct correlation between the consumption of fatty foods and cholesterol levels in the body. The hormones that make you, you (estrogen, progesterone and testosterone) have cholesterol as their precursors. These hormones are known as steroid hormones and are not stored in the body. They are produced as needed. This, therefore, implies that we need a steady availability of cholesterol so de novo synthesis of these hormones can occur as necessary.

So What Exactly Makes Cholesterol So Bad If Their Role in the Body Cannot Be Compromised ?

Just like any other biomolecule, cholesterol is transported in blood. Considering the fact that the blood generally facilitates the transport of hydrophilic molecules, a hydrophobic molecule like cholesterol would need to be transported in association with a hydrophilic molecule. This is where lipoproteins come in. Lipoproteins transport cholesterol in the bloodstream. We have different classes of lipoproteins and they are made up of triglycerides, apolipoproteins and cholesteryl esters in addition to cholesterol. All these are transported in one package. The gag is, cholesterol is transported from liver to cells and from cells to the liver all through blood (obviously). The low density lipoprotein (LDL) transports cholesterol from the liver to the sites of supply (cells).

The high density lipoprotein (HDL) are known to transport cholesterol from the blood to the liver for elimination as bile acids. This is known as reverse cholesterol transport and is very important in preventing the deposition of fats which can lead to the cardiovascular disease. This has given rise to good cholesterol which is the HDL transported cholesterol (simply HDL-cholesterol) and bad cholesterol which is the LDL-transported cholesterol (simply LDL-cholesterol). The LDL-cholesterol has been hugely implicated in coronary heart disease. This is because it is heavily involved in the mechanism of atherogenesis. LDL-cholesterol in the course of transporting cholesterol to cells is known to deposit some as plaques along the walls of the arteries they go through. This causes the walls to thicken and with time they begin to narrow. This thickening and narrowing can lead to blockage of these arteries causing the flow of blood to be impeded and possible risk of the arteries undergoing rupture. This ultimately leads to atherosclerosis.

When this condition gets severe, coronary artery disease is seen to occur.
HDL-cholesterol does the opposite job. It scavenges free cholesterol in blood, with these plaques inclusive, taking them to the liver for elimination. The problem in CAD is, LDL-cholesterol leaves more plaques than HDL can transport back and this results in atherosclerosis. I guess at this point you conclude that cholesterol is to blame but would the next section convince you otherwise ?

Apolipoproteins Should Take the Blame Too

This review revealed the roles of apolipoprotein in CAD. Apparently, Apolipoprotein E plays a huge role in clearing cholesterol from blood. It does so in the form of chylomicrons, Very Low Density Lipoproteins (VLDL) and intermediary density lipoproteins (IDL). These are also huge carriers of cholesterol so it is no surprise that they are implicated in the formation of atherosclerotic plaques. Their clearance from blood depends largely (I mean batshit largely) on the efficiency of apolipoprotein E.

So well, what happens that CAD occurs despite having these ApoE guys around ? It is basically what we like to call, in biochemistry, genetic polymorphism. It is a condition where more than one allele occurs for a particular gene and at a frequency of at least 1% of a given population. This means that each allele of a gene must be observed in more than 1% of a given population for that gene to be considered polymorphic. I guess with this explanation you can agree with me that the genes that control your hair color are polymorphic right ? Rightly so.

This genetic polymorphism leads to the existence of isoforms (proteins that perform similar functions but are made up of different amino acid sequences). These isoforms may perform similar functions but they do so at varying efficiencies. The three common ApoE protein isoforms are; Apo E2, Apo E3 and Apo E4. Apo E3 has been shown to be more efficient in clearing IDL, VLDL and chylomicrons from blood. This is followed by Apo E2 with Apo E4 having the least efficiency. What this implies is that individuals who possess the Apo E3 gene are less at risk at developing CAD. Individuals with Apo E4 are more at risk. This apparently makes apolipoprotein E genetic polymorphism more implicated in the development of CAD than cholesterol.

Apo A-1 is hugely involved in reverse cholesterol transport and facilitates the clearing of cholesterol from blood by HDL. It ensures that cholesterol is eliminated without eliminating HDL as this is needed by the body for reverse cholesterol transport. Mutations in this Apo A-1 protein have been noticed in individuals with Apo A-1_Milano being the most extensively studied. Individuals with this Apo A-1_Milano mutated gene have an unusual protection against cardiovascular disease and this has been attributed to the high efficiency of this mutated gene in assisting cholesterol clearance from the blood.

Well, how about individuals that somehow got a less efficient protein as a result of mutation ? They are at more risk of CAD apparently.
This has led to the argument on whether apolipoproteins or cholesterol should be measured in determining the risks for cardiovascular diseases. I personally think measuring apolipoproteins would be much more reliable but heck, it is expensive. So it all boils down to your pocket.

Final Thoughts

Cardiovascular disease (CVD) kills and it does so daily and in numbers. It is the leading cause of death. I mean WHO shows that 17.7 million people die from CVD every year and it is the leading cause of death worldwide. Apparently, avoiding sedentary lifestyles and watching our diets would go a long way to make us live longer. But what are we to do about an apolipoprotein genetic polymorphism ? Considering that we have mapped out the human genome successfully and this has been vital in the understanding of many diseases, we are still yet to implement sure fire ways to edit genes. Maybe CRISPR/cas9 will go a long way in achieving that. That is not the argument today anyway. Cholesterol or Apolipoprotein who would you blame in CAD ?

References

^{(1)https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3284229/ (2) https://www.bmj.com/content/319/7224/1523.short (3) http://circ.ahajournals.org/content/74/4/758.short (4)https://www.degruyter.com/view/j/cclm.2003.41.issue-9/cclm.2003.181/cclm.2003.181.xml?intcmp=trendmd (5) https://en.wikipedia.org/wiki/Atherosclerosis (6) https://cardiab.biomedcentral.com/articles/10.1186/1475-2840-11-36 (7) http://journals.sagepub.com/doi/abs/10.1191/096120300678828235 (8) https://www.sciencedirect.com/science/article/pii/S0925443912001160 (9) https://europepmc.org/abstract/med/2403935}

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