Sunday, February 07, 2010

Lipoprotein(a) is oxidised cholesterol

If you want someone with serious expertise on the separation of plasma lipids using an ultracentrifuge then Krauss, obviously, is your man. Author number nine out of twelve on this next paper. He was, obviously, their man too.

If you want to look at oxidised lipids in lipoproteins you need an antibody which locks on to oxidised lipids but not to undamaged lipids. This is called E06. It is quite specific and only binds to the phosphocholine residue of an oxidised phospholpid. It's probably the most commonly used antibody for detecting oxLDL. Or what people thought was oxLDL until this paper came out.

What did this group do? All sorts of things, most of them very clever in deed.

Let's scream through the results. First they took an antibody to Lp(a) and pulled the Lp(a) out of plasma with it. E06 reactivity was pulled out along side Lp(a).

They got Krauss to spin some lipids and found, lo and behold, E06 reactivity separated out ONLY with the Lp(a) fraction.

They took some LDL and oxidised it artificially with copper ions. Then they offered it a choice of Lp(a) or native LDL to share lipids with. Not only did E06 reactivity jump out of the oxLDL and in to Lp(a), it ONLY jumped in to the Lp(a). None jumped from copper oxidised LDL to native LDL. None would leave its Lp(a), even to go to another Lp(a).

They went on to check if Lp(a) is just susceptible to oxidation in its own right, by looking for malondialdehyde-lysine residues. It's not oxidised itself. It just collects oxidised lipids. The antibody for malondialdehyde-lysine is E14. It ignores Lp(a). However the E06 antibody to oxidised phospholipid not only recognised Lp(a) but also apo(a) alone, presumably both from sources where they have had access to oxidised lipids.

The implication from this is that while some of the oxidised phospholipids are in the lipid particle of the Lp(a), a big chunk are also bound to the apo(a) protein.

The group feel that apo(a) initially captures oxidised phospholipids from the aqueous plasma phase and they are then transfer over several hours to the lipid droplet.

EDIT: I miss read this, the lipid drop captures the oxidised phospholipds and then they get arranged on the apo(a) glycoprotein. This may have some relevance to apo(a) isoforms, Lp(a) levels and vascular injury.

They doubt that Lp(a) really goes around stealing oxidised lipids from oxLDL particles. What they suspect is happening is that whenever oxidised lipids are released from damaged tissues, Lp(a) is the mop which mops them up. They probably never get as far as native LDL.

As far as they are concerned Lp(a) IS oxLDL. And oxLDL IS Lp(a).

Do tissue damage, the liver makes a sponge for oxidised tissue lipids. Probably many more oxidised lipids than E06 recognises.

You have to wonder whether the liver senses free oxidised lipids in the bloodstream and makes apo(a) in response to them (almost certainly the case, because Lp(a) spikes after injuries such as percutaneous cardiac procedures, where everyone expects oxidised lipids to be mechanically released without dietary warning). Or whether, as in the Finland intervention, volunteers do something grossly stupid such as reducing the fat content of their diet. And the liver pre-empts...

Probably a bit of both.

So, Beth, you asked in the comments section of the last Lp(a) post:

What does Lp(a) actually do?

It preferentially accumulates oxidised lipids and binds them in a form where they cannot be immediately excreted from the plasma. It also puts a great big sticky label on them that allows them to firmly bind to damaged tissue.

Only Lp(a) does this.

Only in humans and related apes. Oh, and in mice genetically engineered with both human apoB100 and apo(a) in combination. Of course.


That too is an interesting question.



Unknown said...

As someone with high Lp(a), > 60mg/dL, I am reading your blogs with a lot of interest. Of course, some of the stuff is very technical in nature and therefore I have not been able to understand much.

Could you summarize for a lay person like me the following :
How bad of a cardio-vascular risk factor is Lp(a) ?
How can people with high Lp(a), mitigate the bad effects ?
Does Lp(a) have any beneficial qualities ?

Thanks a lot in advance.


Stephan Guyenet said...

Hi Peter,

So Lp(a) is a marker of oxLDL. That's what I suspected when I looked into it, but I didn't know it physically binds oxidized lipids. Interestingly, they call Lp(a) "atherogenic". That seems like a bizarre hypothesis. Atherogenic means something is causing atherosclerosis, while Lp(a) seems to be trying to prevent it. They said in the paper that expressing Lp(a) in mice increases serum oxPL and decreases atherosclerosis.

It makes perfect sense that saturated fat would lower Lp(a) relative to PUFA, since it's less easily oxidized.

karl said...

This is not surprising - for APO(a) to bind to LDL there has to be a source of energy, so there is more to this that what is in these papers. First, oxLDL stimulates the intima wall and starts an immune response - my guess is that there is likely a messenger that tells the liver to make APO(a) which binds to LDL forming Lp(a). Lp(a) can be further oxidized into oxLp(a). (oxLDL can also be double oxidized - and I would guess the same for oxLp(a)).

Another way of thinking about this is Lp(a) is a kind of LDL so the LOX-1 receptor may also bind to oxLp(a).

So until Lp(a) becomes oxLp(a) would not say that Lp(a) is an oxLDL - Lp(a) is made up of apoB-100 linked by a sulfhydryl bond apo(a) of variable size(isoforms). This bond (See ) is a covalent bond between cysteine groups. My hunch is this bond's energy comes form the LDL being in the oxidized state - reducing the oxLDL to form Lp(a).

So it could be that APO(a) is protective, but my hunch is if one has the wrong isoforms of Lp(a), then Lp(a) isn't protective - it may actually make things worse. (It appears that APO(a) is heterogeneous - individuals produce more than one isoform) But we don't know for sure - this would make Lp(a) the smoke, not the fire and makes me pause about the goal of reducing the level - different interventions may use different methods to reduce Lp(a). We know Niacin increases HDL - which carries antioxidants that can reduce oxLDL - thus less irritation of the intima wall and less messenger to the liver to produce APO(a) thus less Lp(a). Other methods may interfere with the messanger - and this may be good or bad. It may be that we want a drug that would target only the bad isoforms of APO(a) and leave the good APO(a) alone.

oxLDL (as I keep saying) is central to the disease process - it integrates many things that we know - it has great explainative power. IMHO measuring oxLDL should be central in CVD treatment - particularly for people with elevated Lp(a).

The good news is we know some things that lower oxLDL - ( low carbs for one )

If we were testing oxLDL we would know which interventions make a difference to the individual - this is important for as we all have differences in our metabolism. The good news is that the TYP program seems to target several things already that lower oxLDL - I think we could identify more.

Aaron said...

Interesting! I'm pretty sure there was a post at animal pharm showing some individuals with greater longevity with a higher than average Lp(a). And there is still data that shows some people need to lower Lp(a).

I second Karl that we may need to particular subfractions of Lp(a).

Peter said...

Hi Ankur,

I'm looking to post on the benefits of Lp(a) very soon but, as you can imagine, studies purporting to show the benefits of oxLDL/Lp(a) are much rarer than hens teeth. But there are suggestions.

How much of a risk factor? I don't know, but I would suggest that the usual suspects are actually much more of a problem. Corn oil and sugar for a start and possibly carbs in general, if the Bantu are telling us something significant. Or not, if the rural Japanese were healthy subsisting on rice with rice garnished with rice and served on a bed of rice.... There really are too many threads to this to keep any simple logical sequence to it, so things will chop around a bit. Ok, a lot!

Hi Stephan,

It may be the transition from Lp(a) taking up small amounts of oxPL from tissues to the bulk oxidation of LDL in the face of saturates being replaced by omega 6s that requires bulk Lp(a). Perhaps no Lp(a) is bad, some is useful, but huge amounts is outside physiological limits. There a huge amount of thinking still to do on this and until you hit the correct studies, this latest Krauss offering for one, you don't know what you don't know!

Hi Karl

There are lots of ideas there... Apart from the benefits of oxLDL I'm also looking at why humans gather oxLDL in their plasma using Lp(a) when no other species does. Slowly some sort of logic is emerging. I also wonder if the hedgehog Lp(a) equivalent does the same thing, but the chances of that study getting done seems zero! It's a different kringle which gets repeated, so who knows???? There is also a lot to consider about kringle repeat number and risk, another thread!


Peter said...

Hi Aaron,

I think it might actually come down to what Lp(a) is expecting to do with those oxidised lipids. It's not collecting them for fun and you can argue that it is just getting them out of the way, but I doubt it is that simple. They're useful. They get used, especially when you are over 100 years old...


Peter said...

Hi All,

just stuck this edit on. It might matter.

EDIT: I miss read this, the lipid drop captures the oxidised phospholipds and then they get arranged on the apo(a) glycoprotein. This may have some relevance to apo(a) isoforms, Lp(a) levels and vascular injury.

Robert McLeod said...

All this effort regarding cholesterol is getting rather ridiculous. We keep parsing this tree of lipids deeper and deeper and it's always the next molecule that's going to be the causative agent. Then we look at it and figure, nope, that's not it, look again, look harder.

It's sort of like fusion power, always fifty years away.

It's just such an obvious red herring I don't understand why so much energy is still going into the subject (aside from that funded by drug companies anyway).

Anonymous said...


The way I read it, if you assay oxLDL that is a marker for Lp(a) but I am not sure the reverse is true, as I do not think the Eo6 assay is used by labs to detect Lp(a)

So you can predict LP(a) is elevated in those with elevated oxLDL, and you could guess that a person's high Lp(a) might be in response to the need to clear oxPL, but might not. i.e., you could have high Lp(a) without high oxLDL?

I am thinking someone (me) with Lp(a) of 85 and CAC of zero and CIMT of a 30- year old at age 48 and no family history of coronary disease would support that interpretation, n=1 and all that.

Good thing I eat 70% of calories as fat, though.

Anyone feel free to correct me on this.

Anonymous said...

I would hasten to add for those TYP followers, that although Niacin and sat fat consumption can lower Lp(a) modestly, there is not a shred of evidence that lowering Lp(a) per se will make you healthier. Like we saw with the torcetrapid fiasco, pharmacology to lower a number without thinking about the "how" can kill you

Lp(a) so far must be considered a marker. As Peter says, it must be there for a reason.

FWIW, on my mother's side of the family, nonegenarians are the norm. The typical lifespan on my dad's side is only in the 80's though.

Pål Jåbekk said...

Thank you for a great post and a great blog. Wonder if this Lp(a) might have something to do with humans inability to produce vitamin C? Blood platelets and all that.

Dr. B G said...


Bravo -- thank you for your brain. BRILLIANT SERIES. My Lp(a) = 2 mg/dl is in the far L-sextile of Lp(a)


Help I think I need an Lp(a) transplant. Kurt -- let me suck your BLOOD. Don't wanna small dense stuff (on Koolaid). *haa*


And they say... also LDL is 'atherogenic.' *haaa*

We of course know that is incorrect as well.


TYP is low sat and therefore Lp(a) remains uncontrolled and definitely atherogenic. Me, Jake and a few sophisticated nutri sci folks were the only ones promoting saturated fat.

CAC can NOT be regressive under such conditions and that is my observations. Right? (and everyone else in the paleo high fat community)

Statins and zetia both synergistically and independently raise oxLDL and Lp(a) and lower HDL and raise sdLDL.... Mmmhh I think we've hashed through this already...

Are those conditions not clinically atherogenic? Hello they are.


Peter said...

Rob, CVD is all about damage and clotting as far as I can see. The focus on cholesterol is, as it always has been, bizarre. You just have to look at the table produced by the Oslo group at the factors which differentiate CVD patients from non CVD patients at similar cholesterol levels.

Kurt, very interesting information, thanks for sharing.

Hi Pål,

I'll kick this idea around soon. It has some logic and supportive associations. It would be nice to know if the same apes/humans who have apo(a) are the ones which lack ascorbate. I'll see if I can find this data but I'll bet it won't be too easy to pull out (for me anyway)...

G, you're crazy. I like it.


karl said...

Another take on this:


This paper is also interesting and seems to support other conclusions.

Oxidized Phospholipids, Lp(a) Lipoprotein,and Coronary Artery Disease

Like to know your take on this..