Tuesday, 4 March 2014

ApoE - a quick look under the bonnet

The purpose of posting all that I have found on Apolipoprotein E is (a) to clear my thoughts and (b) to possibly save someone (E4 club members?) some time. Searching the internet for information on ApoE can be a frustrating exercise, assuming you want something other than the standard rubbish.

Following on from my ApoE confession, today I’m going to provide a layman’s explanation of what Apolipoprotein E is, and why you might care.

In a general sense (for simpletons like me), ApoE is a protein made up of 299 amino acids and it is synthesised by (spat out of) many organs, but mainly your liver and your brain. You could think of ApoE as the captain of little shipping vessels (lipoprotein particles) that flow through your body. Here’s a pretty picture of a lipoprotein particle that may help:

As you can sort of see, lipoprotein particles carry lots important stuff like cholesterol, triglycerides (fats) and fat-soluble vitamins and they transport them to where they are required for things like cell regeneration and maintenance, hormone production and immunity function.

The lipoprotein particles that the average Joe Blow might be familiar with are Low Density Lipoproteins (LDL) and High Density Lipoproteins (HDL) - often mistaken for ‘bad and good cholesterol’, but that’s a completely different and insanely boring story. So I won't tell it.

Apart from LDL and HDL there are also IDL (intermediate) and VLDL (very low density) and chylomicrons. I won’t go much further on this, but when you are looking at ApoE it’s important to note that as you move from chylomicrons to VLDL to IDL to LDL, the size and the amount of triglycerides within is decreasing and the amount of cholesterol is increasing. 
 
source: http://eatingacademy.com/
Back to ApoE
When I referred to ApoE as the “captain of the ship”, I meant that once ApoE is synthesised by your liver or brain (mostly) and binds itself to a lipoprotein particle (preferentially depending on the type of ApoE), it will then be a determining factor in where that particle goes and what happens to it.

It does this because it acts a ligand (a connector) to the LDL and other cell receptors. The LDL receptor family is another fascinating ‘thing’ that the cells of our body use to get that important cargo from the lipoprotein particles.

The cells of our body produce the receptor, the lipoprotein particle is cruising past with an ApoE on it and lots of good stuff inside it. The ApoE binds with the receptor and the cells get what they need. 

The ApoE is perhaps the drug dealer, and the cells are desperate for a fix of what they're carrying. Or something like that. For the purposes of this amateur lipidology lesson; ‘magic happens’ and our bodies get something out of it, in part due to ApoE. 

One (indirect, you could say) function of ApoE is to clear lipoproteins from your blood plasma, and anything those particles may have been carrying at the time.If you’re like me and prefer pretty animations to complex wordy explanations, then you may enjoy this that I linked to in the first post. That animation can get stuck sometimes, and I couldn't be certain it's 100% accurate, so be patient and non-pedantic.

ApoE is polymorphic
Which in English means that there are different types, the main ones being ApoE2, E3 and E4. Humans have an ApoE profile that is a combination of two “alleles”. An E3/E3 profile is most common, but you may also be E2/E4, E2/E3, E3/E4 or E4/E4.

As you can see from the table below, the ApoE only differ at sites 112 and 158 of the (299 amino acid) protein:
E2
E3
E4
Most animals including apes
amino acid at site 112
Cysteine
Cysteine
Arginine
Arginine
amino acid at site 158
Cysteine
Arginine
Arginine
Threonine (at site 61)

Like a lot of things, it’s your parents’ fault
It seems that you get one ApoE allele from each of your parents. I’m E4/E4, so to point out the obvious, it follows that my kids have at least one E4 allele. But given that their mother has ridiculously low plasma cholesterol, I guess that they are most likely E3/E4. Possibly E2/E4, but less likely given E2’s rarity.

Fascinating or what?

So, finally getting to some sort of point
Your particular ApoE profile matters. It matters because the ApoE alleles behave differently – E4 preferentially associates with the triglyceride-rich VLDL and chylomicrons whereas E2 and E3 and tend to cling more to the cholesterol-rich LDL and HDL particles.

Why? Another boring story to do with salt bridges, N and C terminals and other such biochemistry nonsense1. What matters to me is what happens as a result of these ‘preferences’ but the geeks among you may find this interesting:
Source: reference 3
Another observation worth noting here is in regard to the ApoE alleles’ ability to bind to the LDL receptors. It sounds like E2 is pretty hopeless at it, which is thought to be why E2 people tend to have low cholesterol. 

In contrast, E3 and E4 play very well with the receptors and E4 is particularly adept at clearing VLDL and chylomicrons from your blood. 

As far as I can ascertain, the theory espoused by SPILCs seems to be that E2 = more LDL receptors = less LDL plasma cholesterol. E4 = fewer LDL receptors = more plasma LDL cholesterol2.

I’ll stop here because I want to break the topic up into digestible chunks. But before I do, I want to pre-empt the next post by saying I think the ApoE/cholesterol relationship is an interesting observation, but it doesn't really tell us much in terms of ApoE’s role in certain health conditions. 

At least not if you're under the impression that cholesterol is good for you. If, on the other hand, you believe high cholesterol is the cause of heart disease, Alzheimer's and all sorts of nasty ailments, then the ApoE relationship will be terribly convenient for you.

References
1. Nguyen et al - Molecular mechanism of apolipoprotein E binding to lipoprotein particles, 2009.
2. Schiele et al - Apolipoprotein E serum concentration and polymorphism in six
European countries: the ApoEurope Project, 2000.
3. Egert et al - ApoE genotype: from geographic distribution to function and responsiveness to dietary factors, 2012.

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