Tuesday, February 09, 2010

Lipoprotein(a): 7-ketocholesterol and cancer

This group did lots and lots and lots and lots of very, very, very clever things. So many, so complex and so clever that I'm not going to try and discuss them all. I was stuck with having to read them all because of the big lump of truth that they tripped over without apparently commenting and I had to look for any justification of the actual conclusions they came to! It's one of those papers where you can't tie the discussion to the results...

This is the executive summary to let me get to the holes in the study.

They found that oxLDL acts on cancer cells in tissue culture to induce two specific changes. The first was the induction of autophagy. This is the housekeeping process of clearing out the odds and sods of damaged and non functional proteins which accumulate with aging. This is a Good Thing, classically induced by ketosis. Good old beta hydroxybutyrate is the classic trigger. So, apparently, is oxLDL!

Obviously, if you are certain that oxLDL causes cancer, you have to consider that any Good Thing happening in bad cancer cells is a Bad Thing for the organism in general. There is no doubt that oxLDL does induce autophagy in cancer cells. This is purported to encourage super cancer cells to develop. These are what I was looking for in the results.

The second thing which oxLDL does is to induce apoptosis in cancer cells. Generally, death is considered to be a Bad Thing from a cancer's perspective. For the organism affected by cancer cells, apoptosis of those cancer cells might be considered a Good Thing.

I dunno.

Perhaps you could say that oxLDL is really Good all round, the cancer cells can die with the happy satisfaction that they had dusted the cupboard under the stairs and emptied the rubbish bins before they committed suicide and the organism is happy to lose the cancer?

There is an unspeakable amount of detail about cell pathways involved but the bottom line is free radicals, ROS. Some ROS equals autophagy, lots equals apoptosis.

OxLDL causes lots of ROS.

Now, if you ignore the discussion and introduction, both of which are exercises in cognitive dissonance, and go to the results you can play hunt the super squeaky clean autophagic cancer cells. Until you are blue in the face. They're not there because they are all either dead or looking VERY sick. No one mentioned finding sleek autophagous cancer cells. Just dead ones.

The action of oxLDL on cancer cells is to kill them. There was no other finding noted on the cellular level, using a microscope. OxLDL, especially the 7-ketocholesterol component, is a potent apoptosis inducer in cancer cells. Quite how this can be a Bad Thing, as expressed throughout this paper, is beyond me.

But there are a series of snags.

OxLDL also induces apoptosis in cultured human umbilical vein endothelial cells. This is undoubtedly a Bad Thing from the CVD point of view. Like Really Bad.

So perhaps oxLDL is really the cause of arteriosclerosis?

It's a nice idea but there really isn't a lot of oxLDL in the blood of any species. In humans it's bound to Lp(a) and in all other species it is present at the lower limits of detectbility. Let's just go back to the Bergman/Krauss/Tsimikas paper and recap:

"In individuals with low Lp[a] levels, there is a corresponding low level of OxPL/apoB, suggesting that in the absence of Lp[a], these OxPLs do not accumulate on plasma apoB-containing lipoproteins other than to a minor degree. A similar situation exists with most animals that we have studied (32, 33). For example, in mice with marked hypercholesterolemia, a situation in which OxPLs recognized by E06 are abundant in the arterial tissues (and probably elsewhere as well), the levels of OxPL/apoB in plasma are very low, and often just at the level of detection of our assay (33). In contrast, Lp[a]-transgenic mice have very high OxPL/apoB levels, even in a C57BL/6 background without obvious atherosclerosis (34). Presumably, this reflects the generation of such OxPLs as a component of normal physiological processes. Lp[a]-transgenic mice express both human apoB-100 and apo[a] and thus can form a true covalent Lp[a] similar to that found in humans (34). Mice expressing high levels of human apoB-100 alone, or apo[a] alone, nevertheless have very low levels of OxPL/apoB (34), suggesting the need for an intact Lp[a] to enable preferential binding of OxPL."

So when you take some native LDL, cook it with copper sulphate and then pour the resulting mess of goo on to cultured cells on a petridish you are really getting a handle on what is happening in the real world of human cardiovascular disease aren't you? Like yeah.

In the real world the oxidised lipids of oxLDL rapidly transfer to Lp(a) (in humans, apes and transgenic Lp[a] mice) or (in all other species) they are excreted, presumably by the liver. Either way, they don't hang around.

Lp(a) has a large sticky moiety which binds to fibrin and proteoglycans. It's not going to see either of these in healthy vascular tissue. Delivering 7-ketcholesterol to the damaged tissue around a cancer cell might be a bit of a magic bullet. It's hardly surprising the body makes lots of apo(a) when the liver picks up markers that you have cancer.

Delivering it to damaged vascular tissue, where fibrin or proteoglycans are exposed, might be good or bad. Probably good in view of a number of other oxidised lipid products present in Lp(a). But if the damage is on going and severe it seems a little unfair to blame the sticking plaster for the damage.

But I would maintain that circulating Lp(a) through healthy tissue has NOTHING in common with pouring copper-oxidised LDL on to cultured vascular smooth muscle cells or endothelial cells.

I suppose at some stage we have to talk about the natural arteriosclerosis which occurs in aged rats and rabbits, but there is so much more of interest about Lp(a) and so little research published to work from...


BTW Barry Groves has an interesting article by Wayne Martin on the role of Dipyridamole in cancer management. It has a nice description of cancers and fibrin which fits neatly with Lp(a) being a potential anticancer stratagem based on targeting blood clot with an apoptosis inducing agent.


Daniel said...

Couldn't this result be explained by making a distinction between things that are god once you already have cancer (oxidation, radiation, chemical toxicity, etc) and things that are good to prevent cancer from forming in the first place?

Robert McLeod said...

Hi Peter:

Why not oxidize LDL the natural way, with a heat shock protein?

Byrne, 1999

karl said...

Very interesting blog - oxLDL is bad for cancer cells and arteriy cells.

In case this is helpful I've got some Lp(a) notes at


and a few oxLDL notes at:



v/vmary said...

this is off topic, but since your focus is on 'high fat nutrition', i wanted to throw this study out there to see if it would interest you to read and comment on.

researchers were looking at factors influencing omega 3 levels in blood. they found that oily fish intake and omega 3 supplementation did not account for 100% of omega 3 blood levels ( if i remember correctly, i think they accounted for 47%). there were other factors involved:

"Other significant independent determinants positively associated with the Omega-3 Index were age (+5.3% for a 10 year increase), and a history of high cholesterol (+8.1%)"

the 'high cholesterol' jumped out at me. could it be that having a high level of good cholesterol somehow facilitates higher levels of omega 3 in the blood?

sorry to be off topic. -v/mary

v/vmary said...

this is the study:


Raodrunner said...

Peter-this is off topic as well but I've been reading through your blog archives and your post on physiologic insulin resistance peaked my interest due to my own situation. I recently had blood tests done and am a little confused. My lipids were all excellent but my blood glucose was 102 and my HgA1c was 5.4%. My insulin was <2 (all fasting). This is all while working out hard three times per week doing weight training and eating partially paleo. I do have a bowl of oatmeal in the morning and a few times per week will have an increased carbohydrate meal. According to your post, I may be experiencing some insulin resistance due to fat mobilization (I have been decreasing weight some recently but am pretty lean at a body comp of 7.1% body fat). I am surprised at my HgA1c. It is barely normal and would suggest that my 102 BG is having an effect. Could I be overtrained or be eating a too low calorie diet (I've been losing weight) with carbs a little too high? Any thoughts would be appreciated. Thanks.

Pai said...

Peter -- Have you seen this new report on 'bad cholesterol' not being so bad after all?


The truth is getting out perhaps, eh?

Clayd said...

It seems that these 2 recent papers on fructose clearly show that it is not dangerous except in high doses. It may even be beneficial if used moderately.

Alan Aragons recent article about fructose alarmism:

Here is a critical interpretation of the Jakobsen meta-analysis that may be of interest:

Peter said...

Hi All,

I might get to comments through today with some luck (lots to links to read) but I've put a quick reply up for you, Clayd, as the next comment


Peter said...

Hi Clayd,

The Burdock Group


You want it, they'll get it for you! From the abstract:

"A systematic assessment of the strength and quality of the studies and their relevance for healthy, normal weight humans ingesting fructose in a normal dietary manner has not been performed. The purpose of this review was to critically evaluate the existing database for a causal relationship between the ingestion of fructose in a normal, dietary manner and the development of hyperlipidemia or increased body weight in healthy, normal weight humans, using an evidence-based approach. The results of the analysis indicate that fructose does not cause biologically relevant changes in TG or body weight when consumed at levels approaching 95th percentile estimates of intake."

Transaltion: "People who are fructose tolerant do not develop fructose poisoning when fed fructose in amounts which do not produce fructose poisoning in those individuals"

Ref 2: This is a meta analysis of studies excluding HFCS (why?), paid for by:

"We are grateful to Julian Stowell, Danisco Sweeteners (Redhill, United Kingdom), for commissioning the review.

The authors' responsibilities were as follows—GL: the literature search; extraction, analysis, and interpretation of data; and the writing of the manuscript; and RT: independent search and extraction of data from the literature. Fructose is produced commercially by the organization that commissioned this study, Dansico Sweeteners (United Kingdom). GL holds shares in Independent Nutrition Logic Ltd, and, at the time of this study, RT was employed by Indepdent Nutrition Logic Ltd. Independent Nutrition Logic Ltd is an independent consultancy that takes commissions from many organizations, a full list of which may be found at www.inlogic.co.uk."

The blog about Lustig's presentation has a number of valid points and a number of invalid ones. Aspects of Lustig annoyed me too. I would also add that I certainly don't see fructose in isolation as the cause of metabolic syndrome. I've put my core ideas about hepatopathy and hyperinsulinaemia up in the series about cirrhosis. You need a global view. But fructose and/or alcohol are still core to the problem, as far as I can see. And a great deal of what Lustig has to say is correct. Even if he is a little self confident. OK, smug.

First comment from that last blog post includes this:

"MR, you do rather go on, don't you?"

Too right! There is just too much to go through here. How can anyone see humans as being adapted to green leaf veggies and PUFA plus olive oil? And if weight loss is so good why does this happen:


"In this population of older individuals, weight loss predicted increased all-cause mortality risk not explained by covariates."


"Among this Indian rural population, mild to severe leanness (BMI < 16 kg/m(2)) and weight loss were important determinants of mortality, especially from chronic respiratory diseases, while overweight and above (BMI > 23 kg/m(2)) did not show any detrimental effect."


"The hazard ratio for men for all-cause mortality with a 10-year BMI decrease of 2 kg/m(2) versus a BMI increase of 1 kg/m(2) was 2.09 (95% CI, 1.56-2.81)."



"Weight loss among the overweight or obese seemed hazardous to survival."

MR's excellent final comment:

"And most people should lose weight!"

I would add: If they want to die.

This is a concern to me when people are struggling to lose weight and having a hard time of it. Weight loss for health is a very, very tricky subject, especially in the elderly. If weight loss is effortless on the OD, it's probably fine. If it's a struggle we have to ask what we really want: A longer life or a smaller coffin?


Peter said...

Hi Daniel,

I need some logic to this. My basic suspicion is that Lp(a) is always good re cancer and the whole atherosclerosis aspect is another subject. I'll probably go to the absolute basics of atherosclerosis sometime soon.


Just to be devils advocate I would suggest that LDL has been evolved as part of the innate immune system and that its oxidation in response to chlamydial stimulation is exactly what it should do as part of dealing with the chlamydia. Need to get some more detail about Dr Ravnskov's hypothesis on infection, LDL and immunity for this one.


There is so much on your site, I'm working my way slowly...

Hi Mary,

I have a reference somewhere, unable to locate it despite trying, that saturated fats improve the absorption of omega 3s. I think it's saturated fat rather than cholesterol...


Hmmm, so now it's down to sdLDL. When will it come to purple spotted LDL? That psLDL is the real killer... But at least they are realising that statins are a waste of time, health and money!

Peter said...

Hi Raodrunner,

The main thing you have to ask is how long your red blood cells live. Check Stephan's posts on his HbA1c



The FBG could be physiological insulin resistance, and the obvious solution is to look at post prandial blood glucose, say at 30, 60 and 90 minutes after a LC or moderate carb meal. If you are spiking above 140mg/dl for any period of time something is wrong. If not you can assume you have long-lived RBCs and your HbA1c is normal. Lots of things do actually influnece HbA1c beyond blood glucose, so do some checking...


Daniel said...

I was only talking about oxLDL, not LP(a). Sorry for the confusion. I think there is a general suspicion that oxidants fight cancer (e.g., high dose intravenous vit C, selenite, maybe rancid fish oil, etc.)

Peter said...

Hi Daniel,

I'd just say that oxLDL is Lp(a), or carried by it. Of course you can have some Lp(a), because most of us do, and not have any oxidised phospholipids on it. But the point of the Krauss paper was that oxLDL as an entity in plasma doesn't seem to exist. In humans the oxPLs transefer to Lp(a) and in non Lp(a) species they are excreted. We accumulate them on Lp(a) for a reason, not because we can't excrete them in the way a mouse does...

I don't really do antioxidants, the intervention studies like WHEL and PPT don't support them, natural or artificial. I do have a lot of time for ascorbate at high dose, given IV, as chemotherapy. I doubt this has anything to do with antioxidant effects or the normal physiological functions of ascorbate.


Daniel said...

That was my point -- pro-oxidants (like extremely high dose C, only achievable by IV, selenite, etc) can have cytotoxic effects on cancer. My thought was that oxLDL may be another example of that principle.

Peter said...

I guess so. You could argue that the function of Lp(a) is to gather up a pro oxidant and deliver it specifically to where it is needed, keeping it away from where it's function is not needed...


Alice Thomas said...
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