Saturday, April 26, 2008

Lipoprotein(a) and genetics

There's a diagram of the structure of human Lp(a) here. The apolipoprotein(a) molecule is the curvy bit partly wrapped around the lipid particle. The section which varies on a genetic basis is the number of repeats of the kringle IV type 2 (shown in black). There can be as few as 10 repeats or more than 50. The rule of thumb, within a given population, is that the lower the number of repeats there are, the higher your total plasma Lp(a) is likely to be. NB comparisons between populations are notoriously difficult. Better control your variables and stick to one population.

It almost looks as if the liver wants a certain number kringle IV repeats in the circulation. If there aren't many kringle IVs in the gene, the liver puts more whole protein molecules out to get the number up. Each protein is attached to a single LDL cholesterol particle. Short repeats mean more individual apo(a) proteins are needed to get the number up, which means a higher Lp(a) concentration. It's not a complete equalisation of kringle IV repeats, but that's the general organisation.

The vegetarian Bantu have two things which are special about their Lp(a).

The first is that, despite considerable intermarriage with fishing Bantu, they are genetically short on the kringle IV repeat front so, naturally, they produce more apo(a), attach each to an LDL, so have higher Lp(a) levels across the board compared to their more carnivorous cousins.

The second is that, if you control for this effect by selecting and comparing two genetically apo(a) matched groups, one veggie and the other fish eating, the difference decreases but is still significant.

What can you make of this? The first thing must be that there is a selection pressure to maintain the differences in apo(a) genetics. Either the fishermen don't need much Lp(a) or the vegetarians need lots. I think the vegetarian environment is such that people with high Lp(a) are more likely to survive.

Second follow on is that the extra Lp(a) from the genetics of the vegetarians is not enough. There is some scope for "pushing" Lp(a) levels up or down from the level you might expect from the genetics of apo(a). The vegetarian environment requires higher Lp(a) than the fishing environment.

We know from intervention studies such as DELTA that a simple change of 7% of calories in the SAD from saturated fat to carbohydrate will increase Lp(a) levels by 20%. What does this mean?

If you subscribe to the "Lp(a) is a suicide lipoprotein" theory, you have to conclude that replacing saturated fat with carbohydrate makes your liver want you dead, by 20% more than it did when you ate butter.

Using monounsaturates instead of saturated fats is not quite as bad, the hepatic homicide lipoprotein only goes up by 11%.

The other way of looking at the changes is to suggest that your liver either monitors your macronutrient intake (you think it doesn't?) or some marker of vascular damage. If you do something which is either is outright damaging, or which is sensed as potentially damaging, your liver acts to save your life. If it "perceives" that you need more Lp(a), you get it.

What each of us gets in terms of the genetic number of kringle IV repeats is probably determined by where our personal ancestors lived. Not much we can do about that. What ever we do to tweak this background level of Lp(a) production is up to us.

From the DELTA study it's pretty clear that no one is going to drop their Lp(a) by eating "healthy" monounsaturates or carbohydrate. From the fish oil study we can see that you won't get any joy from adding omega 3 fatty acids either. I've not seen the effect of omega 6s on Lp(a), but I'd guess they're probably as bad as carbohydrate.

As I see it Lp(a) is a very interesting lipid. I think it's hard to get much information from a single measurement in isolation, but changes in Lp(a) probably give you marks out of 10 for your changes in food choices. "Healthy" oils and carbohydrate score you zero. These are likely to damage your vascular system as judged by your liver's increased output of Lp(a). A surrogate for vascular damage would be the increasing blood pressure with age seen in the vegetarian Bantu, probably related to their 82% carbohydrate diet, and so they will need more Lp(a). They get it.

Down at 70% carbs the fish eating Bantu cope well and don't have degenerating arteries to raise their blood pressure, so they don't need so much Lp(a). They don't make it.

I'd predict that substituting beef dripping for both carbohydrate and olive oil would give you the lowest Lp(a) concentration within your genetic window.

Peter

12 comments:

jay1000000 said...

Peter I have been trying to contact you butI could not find your email address anywhere on teh site. Anyway I am looking for a link to a website that I found on your blog. I think I found it when going through your profile page a while ago (where you have a link set up about some guy Rico). Now I cannot find the link and it is bothering me. The link was to a website that had a philosophy that humans should eat a high fat diet with fruit. Do you know what I am talking about?

jay1000000 said...

Peter I have been trying to contact you butI could not find your email address anywhere on teh site. Anyway I am looking for a link to a website that I found on your blog. I think I found it when going through your profile page a while ago (where you have a link set up about some guy Rico). Now I cannot find the link and it is bothering me. The link was to a website that had a philosophy that humans should eat a high fat diet with fruit. Do you know what I am talking about?

Peter said...

Not sure on that one jay, perhaps it was the link to Seth Robert's blog and the Shangri-La diet? I never got chance to really follow that one through.

I can't find the comments about VNV nation and Rico either! Search engine only covers the main text....

Peter

JohnN said...

Peter,
I read the fish oil study and came to a different conclusion: HDL is up while fibrinogen down with same total cholesterol count - that is good.
Why focusing on driving down the Lp(a) count when damage to the intima is what mobilizes Lp(a) to the injured site in the first place?
There are a rainbow of approaches to improve structural integrity of cell membrane including those that are already described by Pauling (ascorbic acid, Lysine, Proline); omega-3; nitric oxide and potassium (lowering blood pressure), replacing carb with SFA to reduce insulin production (anti-inflammation), etc. To that I could also add fasting to promote cell repair and general maintenance.
Gilbert Ling's idea of structured water (associated induction hypothesis) points to the importance of Ka:Na in maintaining the integrity of cell membrane.

Peter said...

Yes, I would certainly agree. The reason I find Lp(a) fascinating is that it appears to give you marks out of ten for whatever changes you have put in place to improve vascular intergity. I think you mentioned elsewhere that the development of a pharmaceutical agent to lower Lp(a) is likely to be catastrophic, this I certainly think would be the case.

I have to say the Na/K ratio implications of Ling's structured water is one of the aspects of the Optimal Diet that gives me a lot of scope for thought/concern. The one aspect of sodium potassium balance that makes me think it might be less important for LC eaters is the co transportation of potassium with glucose in to cells by insulin. It's not an aspect of FFA uptake, which leaves me wondering why, on an evolutionary basis, that insulin/glucose promotes cellular potassium uptake. FFAs don't.... Is there an aspect of glucose metabolism that affects intracellular potassium homeostatsis that FFA metabolism doesn't? Glycolysis is cytoplasmic where as beta oxidation is mitochondrial. Archaeal vs bacterial metabolism????

All suggestion on a post card to.....

Peter

Douglas Porter said...

Dear Jay & Peter,

You can search on the entire blog, including the comments by going to Google screen and clicking "advance search" tab and then in that screen typing in the term sought in the above boxes and the website in the last box on the opening screen. I tried it on the words you mentioned and I found it.

Porter

Peter said...

Thanks Porter,

That works well.

Peter

JohnN said...

"why, on an evolutionary basis, that insulin/glucose promotes cellular potassium uptake."
Plants, fruits, tubers and meats (minimally processed or consumed with the broth) containing plenty of potassium would be my guess. Additionally, glucose uptake into muscle can occur without insulin which only speeds up the rate (Sonksen, Journal of Endocrinology - 2001).
FFA is indeed insulin-neutral but seems deficient in micro/phyto-nutrients. OD appears to be closest to the Inuit diet with plenty of FFA intake and minimal plant-based food. IMO, this may point to some issue with acid-base balance if one's not careful; the Inuit has been known to suffer from osteoporosis.
I happen to think that our caveman may have done better with a more responsive inflammation capability and plenty of Lp(a) production to deal with the inevitable injury and infection.

JohnN said...

"I find Lp(a) fascinating is that it appears to give you marks out of ten for whatever changes you have put in place to improve vascular intergity."
There may be an interesting dilemma if we cannot determine whether those Lp(a) are coming or going.

Peter said...

Hi Johnn,

Did you see the editorial here? The idea of Lp(a) "going" strikes me as an ad hoc hyposthesis of the nth degree. The Lp(a) sticks itself to damaged artery wall. I cannot for the life of me imagine it just sits there. The lipid and the cholesterol will surely get used for something? You then have to have an LDL particle come wandering by and the apo(a) protein leap out of the mass of established clot, cholesterol and necrotic tissue which used to be the arterial wall, covalently bind itself to the LDL particle in the correct orientation then float off to either patch another damage area up or be detected in a lab test as being immunologically indistinguishable form a freshly minted copy...

Only a desperate cardiologist could think that one up! The only reason they had to think of this particular ad hoc is that low fat diets upped the level. They just can't conceive that a low fat diet could really, genuinely be BAD for you. Plus cardiologist are experts at ad hocing of course.

I completely agree that a single measurement is irrelevant, it's the push away from your genetic level that should matter. I can't see any way you could get this unless by a trend analysis on multiple samples with some sort of intervention... Even so, how do you tell when the elevated Lp(a) which is attempting a repair is going to be successful (as in centenarians) or is going to be overwhelmed by the Fanta and low fat donuts?

Peter

There are more posts on Lp(a) cooking but other stuff keeps getting in the way. Had some interesting papers from g.

Barkeater said...

I'm just a dumb yank. What does the expression "marks out of ten" mean?

Peter said...

Hi Barkeater,

It just means whether you have nad correct decisions. Nought out of ten, IHD. Ten out of ten, regression...

Peter