(I was going to give a how-to guide for raising HDL today, but I’ll do that Tuesday; today I want to address some interesting preliminary matters.)

On Tuesday I raised the possibility that the primary function of HDL particles is immune: HDL gathers anti-pathogenic immune molecules and acts as a “Trojan horse” to attach those molecules to pathogens, helping white blood cells find and kill them.

Another Function of HDL: Toxin Clearance

I probably should have mentioned that HDL has another function: toxin clearance. The primary lipoprotein in HDL, apolipoprotein A-I, not only binds to immune proteins, it also can pick up an assortment of toxins, including oxidized LDL.

The liver is the body’s toxin-destruction organ, and I would propose that its toxin transport function is why HDL tends to return to the liver. As this hypothesis would predict, when HDL has picked up oxidative toxins, its reverse efflux back to the liver is enhanced. [1]

Since toxins cause inflammation, removal of these toxins from the vasculature is anti-inflammatory. This is why HDL is said to be anti-inflammatory.

What are the sources of toxins that HDL clears? One review says reverse efflux, i.e. HDL toxin clearance, is triggered by “genetic mutations, smoking, stress, and high-fat diets.” [2] By high-fat diets they mean high-omega-6 diets which create lots of toxic peroxidized lipids. So if you want your HDL to be devoted to toxin clearance, rather than immune defense, eat a lot of soybean or corn oil.

Interestingly, as aging proceeds and health becomes impaired, HDL becomes less effective at picking up toxins and carrying them back to the liver. [2]

My interpretation of this observation would be that as we age, our burden of chronic infections increases. This causes more of our HDL to pick up immune proteins, converting them into pathogen-fighting HDL rather than toxin-clearing HDL.

These pathogen-fighting HDL particles do not go back to the liver. [3] So when HDL gets converted to pathogen-fighting particles, it can no longer clear toxins. Toxins linger in vascular cells and macrophages for lack of HDL transport.

Conventional Wisdom: “Dysfunctional” HDL

I often criticize mainstream scientists and doctors for an anti-natural view of human biology. Mainstream research paradigms neglect pathogens and toxins as the cause of disease, and presume instead that disease results from some malfunctioning of the human body – from genetic mutations, from autoimmune self-attacks, from kamikaze poisoning by evolved entities like LDL particles.

Last September I mocked this attitude in a parable. This week, I was amused to see this attitude at work in the scientists who study HDL.

When HDL particles pick up immune protein complexes and take on their anti-pathogen functions, some scientists call the resulting particles “dysfunctional” or “pro-inflammatory” HDL. [3, 4, 5] This is contrasted to the “anti-inflammatory” HDL that is light, fluffy, fatty and available to carry toxins back to the liver.

The reasoning seems to be that since inflammation is bad, HDL that participates in the inflammatory response must be “dysfunctional.” To me, this is rather like calling white blood cells “dysfunctional blood cells.” After all, white blood cells are pro-inflammatory.

Aside: Why I Don’t Often Use the Word “Inflammation”

This is why I rarely use the word inflammation:  it has a bad connotation, even though it is a natural process involved in healing and immune defense. Like LDL, it has been demonized for its association with disease. Like firefighters who associate with fires, and ambulance drivers that associate with heart attack victims, inflammation should not be blamed for the dysfunction it attends.

Not all anti-inflammatory therapies are good for you. Clearing your body of “dysfunctional HDL” would temporarily reduce inflammation – but it would let pathogens run wild, potentially leading to the fate of Emily’s great uncle.

Can There Be Too Much HDL?

In biology, it’s a general rule that you can get too much of a good thing. The benefits from something usually follow an upside-down U: they increase for a while, reach an optimum, then they fall. Many nutrients are like this: beneficial in small doses, toxic in large doses.

Indeed, our diet is predicated on the idea that we should try to get all good things into their optimal “plateau range.”

It’s also a good rule of thumb that evolution selects for the optimum. Evolution prefers that we be healthy, so the natural evolutionarily selected levels of biomarkers are usually best for us. In general we should eat a healthy diet, and trust that our body will regulate components, like HDL, to their optimal amount.

So that raises the question:  Is it bad to manipulate the body to raise HDL to unusually high levels? Might HDL, like other good things, have a U-shaped benefits curve – so that there is an optimum and raising HDL above that is damaging? Shouldn’t we just live naturally and let our body adjust HDL to whatever level it wants, trusting evolution to have chosen the optimal HDL level for us?

In concrete terms: Is Richard Nikoley’s coconut oil-induced HDL of 133 mg/dl too high?

It’s a fair question!

What Evolutionary Milieu is Our HDL Particle Number Optimized For?

Evolution did select for an optimal level of HDL – that’s why our HDL level is not infinite.

So why did evolution limit HDL? If higher HDL clears toxins and kills pathogens, what would cause evolution to give us too little of it?

A likely answer is that it is costly to produce HDL, and there are diminishing returns to immunity at high HDL levels.

Let’s imagine the Paleolithic environment. Pathogens then were less dangerous. Because the entire global human population was in the hundreds of thousands, human-human transmission was more rare. Without domesticated animals, zoonotic transmission was rare.

Also, food was less available. Today supermarkets are everywhere and people rarely go hungry; but in the Paleolithic the body had to be careful about preserving resources.

So the evolutionary impulse was to conserve resources: the body wouldn’t make more HDL than necessary, since sources for HDL could be better used to scrimp on food.

If this correct, then the optimum HDL level in the Paleolithic was low.

Then the Neolithic came: animals were domesticated and lived near and with humans. People settled in towns, and population density rose. Feces polluted the local water, facilitating pathogen transmission. Pathogens evolved for greater virulence.

In the medieval period, the world’s great civilizations became densely populated. China, especially, became home to hundreds of millions of people living in close contact. These civilizations were subject to the greatest pathogen loads and must have been under strong selective pressure for enhanced immunity, and thus higher HDL levels.

But evolution doesn’t work overnight. Our natural HDL levels may not yet have evolved to their optimum. They may still be undershooting optimal levels.

HDL Epidemiology

If I’m right, then HDL must be undergoing current evolutionary selection for higher levels.

Historically, HDL levels should have been rising since the Neolithic, and rising the fastest in the most densely populated civilizations.

There are other factors too: geography plays a big role. Pathogens flourish in Africa, and in tropical climes generally. Northerly latitudes with their cold winters are low in pathogens.

So let’s consider what the geographic distribution of HDL levels should be, ignoring contributions from diet.

If my argument is correct, populations who until recently lived as isolated, low-density hunter-gatherers – like Australian aborigines, Melanesians and Polynesians – will have the lowest HDL levels, levels similar to those of our Paleolithic ancestors.

Meanwhile, people who have lived for the last few millennia with the highest population densities – East Asians – or the highest disease burdens – Africans – will have the highest HDL.

Europeans, with a favorable geography and middling historical population density, should be intermediate in HDL levels.

What does the data show?

HDL in Kitava averaged 44.5 mg/dl. [6]

For American populations in NHANES III, African-Americans averaged 53 mg/dl and white Americans averaged 49 mg/dl. This is a good comparison because Americans of different races eat similar diets.

In the Beijing Eye Study, Chinese were found to average 62.3 mg/dl, with one Beijing resident having an HDL over 270 mg/dl! [7] In the InterASIA study, however, Chinese averaged only 51.7 mg/dl. [8]

It’s difficult to infer much from this data, since diet and infectious burden affect HDL levels. The lower HDL in Kitava could be due to their higher carbohydrate intake. But overall, it is consistent with my evolutionary hypothesis. Kitavans have the lowest HDL levels, Americans of European descent are intermediate, and African-Americans and Chinese have the highest HDL levels.

What About Within Populations?

If our optimal HDL levels are higher than our “natural” evolved HDL levels, then the rare people with highly elevated HDL – those blessed with genetic variants that increase HDL, or that live the lifestyles that most elevate HDL – should live longest and be healthiest.

Indeed, that seems to be what is observed. As noted on Tuesday, in the VA Normative Aging Study, “Each 10-mg/dl increment in HDL cholesterol was associated with a 14% [decrease] in risk of mortality before 85 years of age.” [9]

Conclusion

There’s little data to evaluate the healthfulness of very high HDL levels, but what data we have suggests that more is better.

There’s also a plausible (to me) evolutionary story for why our optimal HDL levels may be far higher than the ones selected by evolution.

For most biomarkers I would trust evolutionary selection and let my body do whatever it wants; but for HDL I will make an exception. I think we will benefit from dietary tactics that raise HDL levels above the evolutionary norm. And this is especially true for those with infectious diseases.

So my judgment is: let’s be like Richard Nikoley and aim for high HDL. I’ll discuss how on Tuesday.

References

[1] Pirillo A et al. Modification of HDL3 by mild oxidative stress increases ATP-binding cassette transporter 1-mediated cholesterol efflux. Cardiovasc Res. 2007 Aug 1;75(3):566-74. http://pmid.us/17524375.

[2] Berrougui H, Khalil A. Age-associated decrease of high-density lipoprotein-mediated reverse cholesterol transport activity. Rejuvenation Res. 2009 Apr;12(2):117-26. http://pmid.us/19405812.

[3] Feingold KR, Grunfeld C. The acute phase response inhibits reverse cholesterol transport. J Lipid Res. 2010 Apr;51(4):682-4. http://pmid.us/20071695.

[4] Undurti A et al. Modification of high density lipoprotein by myeloperoxidase generates a pro-inflammatory particle. J Biol Chem. 2009 Nov 6;284(45):30825-35. http://pmid.us/19726691.

[5] Smith JD. Myeloperoxidase, inflammation, and dysfunctional high-density lipoprotein. J Clin Lipidol. 2010 Sep-Oct;4(5):382-8. http://pmid.us/21076633.

[6] Lindeberg S et al. Determinants of serum triglycerides and high-density lipoprotein cholesterol in traditional Trobriand Islanders: the Kitava Study. Scand J Clin Lab Invest. 2003;63(3):175-80. http://pmid.us/12817903.

[7] Wang S et al. Prevalence and associated factors of dyslipidemia in the adult chinese population. PLoS One. 2011 Mar 10;6(3):e17326. http://pmid.us/21423741.

[8] He J et al. Serum total and lipoprotein cholesterol levels and awareness, treatment, and control of hypercholesterolemia in China. Circulation. 2004 Jul 27;110(4):405-11. http://pmid.us/15238453.

[9] Rahilly-Tierney CR et al. Relation Between High-Density Lipoprotein Cholesterol and Survival to Age 85 Years in Men (from the VA Normative Aging Study). Am J Cardiol. 2011 Apr 15;107(8):1173-7. http://pmid.us/21296318.