Category Archives: HDL/LDL/cholesterol

High LDL on Paleo Revisited: Low Carb & the Thyroid

One of the more mysterious conditions afflicting low-carb Paleo dieters has been high serum cholesterol. Two of our most popular posts were about this problem: Low Carb Paleo, and LDL is Soaring – Help! (Mar 2, 2011) enumerated some cases and asked readers to suggest answers; Answer Day: What Causes High LDL on Low-Carb Paleo? (Mar 4, 2011) suggested one possible remedy.

On the first post, one of the causes suggested by readers was hypothyroidism – an astute answer. Raj Ganpath wrote:

Weight loss (and VLC diet) resulting in hypothyroidism resulting in elevated cholesterol due to less pronounced LDL receptors?

Kratos said “Hypothyroidism from low carbs.” Mike Gruber said:

I’m the guy with the 585 TC. It went down (to 378 8 months or so ago, time to check again) when I started supplementing with iodine. My TSH has also been trending up the last few years, even before Paleo. So hypothyroidism is my primary suspect.

Those answers caused me to put the connection between hypothyroidism and LDL levels on my research “to do” list.

Chris Masterjohn’s Work on Thyroid Hormone and LDL Receptors

Chris Masterjohn has done a number of blog posts about the role of LDL receptors in cardiovascular disease. His talk at the Ancestral Health Symposium was on this topic, and a recent blog post, “The Central Role of Thyroid Hormone in Governing LDL Receptor Activity and the Risk of Heart Disease,” provides an overview.

His key observation is that thyroid hormone stimulates expression of the LDL receptor (1). T3 thyroid hormone binds to thyroid hormone receptors on the nuclear membrane, the pair (a “dimer”) is then imported into the nucleus where it acts as a transcription factor causing, among other effects, LDL receptors to be generated on the cell membrane.

So higher T3 = more LDL receptors = more LDL particles pulled into cells and stripped of their fatty cargo. So high T3 tends to reduce serum LDL cholesterol levels, but give cells more energy-providing fats. Low T3, conversely, would tend to raise serum cholesterol but deprive cells of energy.

Other Pieces of the Puzzle

Two other facts we’ve recently blogged about help us interpret this result:

We can now assemble a hypothesis linking low carb diets to high LDL. If one eats a glucose and/or protein restricted diet, T3 levels will fall to conserve glucose or protein. When T3 levels fall, LDL receptor expression is reduced. This prevents LDL from serving its fat transport function, but keeps the LDL particles in the blood where their immune function operates.

If LDL particles were being taken up from the blood via LDL receptors, they would have to be replaced – a resource-expensive operation – or immunity would suffer. Apparently evolution favors immunity, and gives up the lipid-transport functions of LDL in order to maintain immune functions during periods of food scarcity.

High LDL on Low Carb: Good health, bad diet?

Suppose LDL receptors are so thoroughly suppressed by low T3 that the lipid transport function of LDL is abolished. What happens to LDL particles in the blood?

Immunity becomes their only function. They hang around in the blood until they meet up with (bacterial) toxins. This contact causes the LDL lipoprotein to be oxidized, after which the particle attaches to macrophage scavenger receptors and is cleared by immune cells.

So, if T3 hormone levels are very low and there is an infection, LDL particles will get oxidized and cleared by immune cells, and LDL levels will stay low. But if there is no infection and no toxins to oxidize LDL, and the diet creates no oxidative stress (ie low levels of omega-6 fats and fructose), then LDL particles may stay in the blood for long periods of time.

If LDL particles continue to be generated, which happens in part when eating fatty food, then LDL levels might increase.

So we might take high LDL on Paleo as a possible sign of two things:

  • A chronic state of glucose deficiency, leading to very low T3 levels and suppressed clearance of LDL particles by lipid transport pathways.
  • Absence of infections or oxidative stress which would clear LDL particles by immune pathways.

The solution? Eat more carbs, and address any remaining cause of hypothyroidism, such as iodine or selenium deficiency. T3 levels should then rise and LDL levels return to normal.

Alternatively, there is evidence that some infections may induce euthyroid sick syndrome, a state of low T3 and high rT3, directly. And these infections may not oxidize LDL, thus they may not lead to loss of LDL particles by immune pathways. So such infections could be another cause of high LDL on Paleo.

Gregory Barton’s Experience

Gregory Barton is an Australian, 52 years old, living in Thailand, where he keeps goats, makes goat cheese and manages a large garden which can be seen on

Gregory left a comment with an intriguing story, and I invited him to elaborate in a post. Here’s Gregory’s story. – Paul

Gregory’s Writing Begins Here

One of the claims of low carb dieting is that it will normalize the symptoms of metabolic syndrome. Blood pressure, blood sugar and blood lipids, it is claimed, will all come down on a low carb diet, in addition to weight. For most people this happens. But there is a significant minority of people on Paleo and other low carb diets whose blood lipids defy this claim. (See the list of low-carb celebrities with high LDL in this post.)

Why should this happen? Why should some people’s lipids fall on low carb while other people’s lipids rise? Suboptimal thyroid might be the proximate cause for lipids rising on a low carb or paleo diet. Broda Barnes and Lawrence Galton have this to say about thyroid disorders:

“Of all the problems that can affect physical or mental health, none is more common than thyroid gland disturbance. None is more readily and inexpensively corrected. And none is more often untreated, and even unsuspected.”  — Hypothyroidism: The Unsuspected Illness

I went very low carb in April in an effort to address metabolic issues, eating as little as 15grams carbohydrate per day. I had great results with blood pressure, sleeping, blood sugar and weight loss. But lipids bucked the trend.

I had expected triglycerides and cholesterol to drop when I cut the carbs, but they did the opposite: They surged. By July my total cholesterol was 350, LDL 280, and triglycerides bobbed around between 150 and 220.

I did some research and found several competing theories for this kind of surge:

  1. Saturated fat: The increase in saturated fat created a superabundance of cholesterol which the liver cannot handle. Also, Loren Cordain has claimed that saturated fat downregulates LDL receptors.
  2. Temporary hyperlipidemia: The surge in lipids is the temporary consequence of the body purging visceral fat. Jenny Ruhl has argued that within a period of months the situation should settle down and lipids should normalize.
  3. Hibernation: The metabolism has gone into “hibernation” with the result that the thyroid hormone T4 is being converted into rT3, an isomer of the T3 molecule, which prevents the clearance of LDL.
  4. Malnutrition: In March, Paul wrote that malnutrition in general and copper deficiency in particular “… is, I believe, the single most likely cause of elevated LDL on low-carb Paleo diets.”
  5. Genetics: Dr. Davis has argued that some combinations of ApoE alleles may make a  person “unable to deal with fats and dietary cholesterol.”

I could accept that saturated fat would raise my cholesterol to some degree. However, I doubted that an increase in saturated fat, or purging of visceral fat, would be responsible for a 75% increase in TC from 200 to 350.

There are two basic factors controlling cholesterol levels: creation and clearance. If the surge was not entirely attributable to saturated fat, perhaps the better explanation was that the cholesterol was not being cleared properly. I was drawn to the hibernation theory.

But what causes the body to go into hibernation? According to Chris Masterjohn, a low carb diet could be the cause. Although he does not mention rT3, he warns,

“One thing to look out for is that extended low-carbing can decrease thyroid function, which will cause a bad increase in LDL-C, and be bad in itself. So be careful not to go to extremes, or if you do, to monitor thyroid function carefully.”

If low carb is the cause, then higher carb should be the cure. Indeed, Val Taylor, the owner of the yahoo rT3 group, commented that “it is possible that the rT3 could just be from a low carb diet.” She says, “I keep carbs at no lower than 60g per day for this reason.”

Cortisol and Getting “Stuck” in Hibernation

So what about temporary hyperlipidemia? Bears hibernate for winter, creating rT3, but manage to awaken in spring. Why should humans on low carb diets not be able to awaken from their hibernation? There are many people who complain of high cholesterol years after starting low carb.

A hormonal factor associated with staying in hibernation is high cortisol. It has been claimed that excessively high or low cortisol, sustained over long periods, may cause one to get “stuck” in hibernation mode. One of the moderators from the yahoo rT3 group said:

High or low cortisol can cause rT3 problems, as can chronic illness. It would be nice if correcting these things was all that was necessary. But it seems that the body gets stuck in high rT3 mode.

James LaValle & Stacy Lundin in Cracking the Metabolic Code: 9 Keys to Optimal Health wrote:

When a person experiences prolonged stress, the adrenals manufacture a large amount of the stress hormone cortisol. Cortisol inhibits the conversion of T4 to T3 and favours the conversion of T4 to rT3. If stress is prolonged a condition called reverse T3 dominance occurs and lasts even after the stress passes and cortisol levels fall. (my emphasis)

What I Did

First, I got my thyroid hormone levels tested. A blood test revealed that I had T4 at the top of the range and T3 below range. Ideally I would have tested rT3, but in Thailand the test is not available. I consulted Val Taylor, the owner of the yahoo rT3 group, who said that low T3 can cause lipids to go as high as mine have and, “as you have plenty of T4 there is no other reason for low T3 other than rT3.”

I decided to make these changes:

  1. Increase net carbs to ~50 grams per day. Having achieved my goals with all other metabolic markers I increased carbs, taking care that one hour postprandial blood sugar did not exceed 130 mg/dl.
  2. Supplement with T3 thyroid hormone.
  3. In case the malnutrition explanation was a factor, I began supplementing copper and eating my wife’s delicious liver pate three times per week.

I decided to supplement T3 for the following reasons:

  • The surge in TC was acute and very high. It was above the optimal range in O Primitivo’s mortality data.
  • I increased carbs by 20-30g/day for about a month. TC stabilized, but did not drop.
  • The rT3 theory is elegant and I was eager to test my claim that the bulk of the cholesterol was due to a problem with clearance rather than ‘superabundance’.

What happened?

I started taking cynomel, a T3 supplement, four weeks ago. After one week triglycerides dropped from 150 to 90. After two weeks TC dropped from 350 to 300 and after another week, to 220. Last week numbers were stable.

Based on Paul’s recent series on blood lipids, especially the post Blood Lipids and Infectious Disease, Part I (Jun 21, 2011), I think TC of 220 mg/dl is optimal. As far as serum cholesterol levels are concerned, the problem has been fixed.

I believe that thyroid hormone levels were the dominant factor in my high LDL. Saturated fat intake has remained constant throughout.

My current goal is to address the root causes of the rT3 dominance and wean myself off the T3 supplement. I hope to achieve this in the next few months. My working hypothesis is that the cause of my high rT3 / low T3 was some combination of very low carb dieting, elevated cortisol (perhaps aggravated by stress over my blood lipids!), or malnutrition.

Another possibility is toxins: Dr Davis claims that such chemicals as perchlorate residues from vegetable fertilizers and polyfluorooctanoic acid, the residue of non-stick cookware, may act as inhibitors of the 5′-deiodinase enzyme that converts T4 to T3. Finally, Val Taylor claims that blood sugar over 140 mg/dl causes rT3 dominance. I couldn’t find any studies confirming this claim, and don’t believe it is relevant to my case. Val recommends low carb for diabetics to prevent cholesterol and rT3 issues but warns not to go under 60g carb per day.

Issues with T3 Supplementation

There are some factors to consider before embarking upon T3 supplementation:

  1. Preparation: In order to tolerate T3 supplement you have to be sure that your iron level and your adrenals are strong enough. This requires quite a bit of testing. I’ve read of people who cut corners with unpleasant results.
  2. Practicalities: T3 supplementation requires daily temperature monitoring in order to assess your progress. People who are on the move throughout the day would find this difficult.
  3. Danger: Once you get on the T3 boat you can’t get off abruptly. Your T4 level will drop below range and you will be dependent on T3 until you wean yourself off. If you stopped abruptly you could develop a nasty reaction and even become comatose.

My advice for anyone doing very low carb

As Chris Masterjohn said, in the quote above, if you are going to do very low carb, check your thyroid levels. I would add: Increase the carbs if you find your free T3 falling to the bottom of the range. It might be a good idea to test also for cortisol. A 24-hour saliva test will give you an idea whether your cortisol levels are likely to contribute to an rT3 issue. It might also be a good idea to avoid very low carb if you are suffering from stress – such as lipid anxiety!

Gregory Barton’s Conclusion

I also think my experience may help prove thyroid hormone replacement to be an alternative, and superior, therapy to statins for very high cholesterol. Statins, in the words of Chris Masterjohn,

“… do nothing to ramp up the level of cholesterol-made goodies to promote strength, proper digestion, virility and fertility.  It is the vocation of thyroid hormone, by contrast, to do both.”

Paul’s Conclusion

Thanks, Gregory, for a great story and well-researched ideas. The rapid restoration of normal cholesterol levels with T3 supplementation would seem to prove that low T3 caused the high LDL levels.

However, I would be very reluctant to recommend T3 supplementation as a treatment for high LDL on Paleo.  If the cause of low T3 is eating too few carbs, then supplementing T3 will greatly increase the rate of glucose utilization and aggravate the glucose deficiency.

The proper solution, I think, is simply to eat more carbs, to provide other thyroid-supporting nutrients like selenium and iodine, and allow the body to adjust its T3 levels naturally. The adjustment might be quite rapid.

In Gregory’s case, his increased carb consumption of ~50 g/day was still near our minimum, and he may have been well below the carb+protein minimum of 150 g/day (since few people naturally eat more than about 75 g protein). So I think he might have given additional carbs a try before proceeding to the T3.

Gregory had a few questions for me:

GB: What if one is glucose intolerant and can’t tolerate more than 60 grams per day without hyperglycemia or weight gain?

PJ: I think almost everyone, even diabetics, can find a way to tolerate 60 g/day dietary carbs without hyperglycemia or weight gain, and should.

GB: What if raising carbs doesn’t normalize blood lipids and one finds oneself ‘stuck in rT3 mode’?

PJ: I’m not yet convinced there is such a thing as “stuck in rT3 mode” apart from being “stuck in a diet that provides too few carbs” or “stuck in a chronic infection.” If one finds one’s self stuck while eating a balanced diet, I would look for infectious causes and address those.

Finally, if I may sound like Seth Roberts for a moment, I believe this story shows the value of a new form of science: personal experimentation, exploration of ideas on blogs, and the sharing of experiences online. It takes medical researchers years – often decades – to track down the causes of simple phenomena, such as high LDL on low carb. We’re on pace to figure out the essentials in a year.

Low Serum Cholesterol in Newborn Babies

Don Matesz, who has embraced low-fat and low-cholesterol dieting, recently stated that “I now consider anything over ~160 mg/dl [to be] excess serum cholesterol” and cited in his support the Cordain-Eaton claims that healthy hunter-gatherers had low serum cholesterol. Of course, we looked at that and found that healthy hunter-gatherers generally had serum cholesterol over 200 mg/dl and that hunter-gatherers with low serum cholesterol generally had high infectious burdens and short lifespans. See:

When Erik referenced our series and asked, “What do you think of the argument that low cholesterol in hunter gatherer populations stems from infections and parasites?”, Don replied:

Mean total blood cholesterol of healthy human neonates is about 72 mg/dl.

Is this due to infections and parasites?

In case this question was not merely rhetorical, let me answer: No.

But it’s an interesting biology question. Why do neonates have low serum cholesterol?

Neonates and Infants

The study that Don cited [1] looked at cord blood from neonates. Cord blood is blood that circulates on the fetal side of the placenta in utero. As soon as the baby is delivered, the cord is cut and blood ceases to circulate.

So the cord blood serum cholesterol of 70.3 mg/dl is really sampling fetal cholesterol – the blood of babies who have never eaten and never breathed.

The not eating part is relevant, because HDL is generated from the metabolism of chylomicrons created in the intestine when fat is eaten, and LDL is generated from VLDL particles that carry excess calories as triglycerides from the liver. So eating generates LDL and HDL. We might expect that LDL and HDL, and thus TC, levels will rise as soon as the neonate starts feeding.

We can check this out by looking at cholesterol levels in infants. The following data is from Japan [2], but any healthy population would give similar results:

Serum total cholesterol in infants, mg/dl, by feeding method

Infant Age Formula-fed Partially breastfed Breastfed
One month 117 142 163
Six months 140 162 194

Source: Tables 2 and 3, Isomura et al 2011.

The key data is in the rightmost column, the breastfed babies. By one month postpartum, TC is 163 mg/dl (“excess serum cholesterol” on Don’s view). By six months, it is 194 mg/dl.

Formula fed babies had a much smaller rise in TC.

To understand the pattern of this data, let’s look at three issues:

  • Why do formula-fed babies have lower TC than breastfed babies?
  • Why do neonates have low TC?
  • Why do breastfed babies end up with TC near 200 mg/dl?

Formula is a lipid-deficient food

Why do formula fed babies have lower serum cholesterol? One contributing factor may be a dietary lipid deficiency.

Human breast milk is rich in cholesterol. One study found that the cholesterol content of human breast milk follows a diurnal rhythm with a low of 140 mg/L during sleeping hours and early morning, and a high of 220 mg/L in the afternoon and evening. Other studies agree that human breast milk always has more than 100 mg/L cholesterol. Babies typically drink 750 mL/day, so a breastfed baby’s daily cholesterol intake is 100 to 200 mg.

Scaled by body weight, this would be the equivalent of 1.5 to 3 grams cholesterol per day for adults – approximately ten times the typical cholesterol intake of American adults.

Clearly, evolution thinks babies should get plenty of cholesterol.

But cholesterol levels in formula are much lower:

Since … infant formulas contain very little cholesterol (10 to 30 mg/L) (Huisman et al., 1996; Wong et al., 1993), it is not surprising that plasma cholesterol concentrations are higher in infants fed human milk than in formula-fed infants.

I guess the formula makers don’t consider cholesterol to be a desirable nutrient. This may be an extremely consequential mistake.

Low TC in Neonates May Have Evolved to Suppress Immunity

So why do neonates have a very low TC?

In addition to fat and cholesterol transport, LDL and HDL both have immune functions. Low serum cholesterol signifies a loss of these immune functions. Normal immune function is associated with TC around 200 mg/dl or higher.

But infants are well known to have suppressed immunity. This is important: if the fetus had an ability to generate antibodies and mount an immune response, it might generate immune attacks against the mother leading to miscarriage.

After birth, a baby’s immune system gradually matures:

A baby’s immune system is not fully developed until he/she is about six months-old. In the meantime, pregnant mothers pass immunoglobulin antibodies from their bloodstream, through the placenta, and to the fetus. These antibodies are an essential part of the fetus’s immune system. They identify and bind to harmful substances, such as bacteria, viruses, and fungi that enter the body. This triggers other immune cells to destroy the foreign substance….

Immediately after birth, the newborn has high levels of the mother’s antibodies in the bloodstream. Babies who are breastfed continue to receive antibodies via breast milk…. This is called passive immunity because the mother is “passing” her antibodies to her child. This helps prevent the baby from developing diseases and infections.

During the next several months, the antibodies passed from the mother to the infant steadily decrease. When healthy babies are about two to three months old, the immune system will start producing its own antibodies. During this time, the baby will experience the body’s natural low point of antibodies in the bloodstream. This is because the maternal antibodies have decreased, and young children, who are making antibodies for the first time, produce them at a much slower rate than adults.

Once healthy babies reach six months of age, their antibodies are produced at a normal rate.

LDL particles, by presenting pathogen toxins to macrophages which can then present them on MHC molecules, play an important role in the generation of antibodies. (See Blood Lipids and Infectious Disease, Part II, July 12, 2011.) Low LDL signifies a reduced ability to generate antibodies.

Low LDL is therefore highly desirable as long as the baby remains in the womb, and in fact LDL levels are very low in utero.

But persistent low LDL after birth is dangerous: it makes the infant vulnerable to infections. Likewise, HDL has important immune functions (see HDL and Immunity, April 12, 2011). So LDL and HDL gradually rise to normal physiological levels, finally reaching a TC of 200 mg/dl after 6 months in breastfed babies – precisely when the babies attain normal immune function.

If TC of 190 mg/dl or higher signifies normal immune function, then formula fed babies are still immune suppressed at 6 months. Extrapolating the rise in TC, partially breast fed babies might achieve normal immune function at 12 months and formula fed babies might not achieve normal immunity until age 24 months!

Immunity Matters for Infant Health

I don’t want to delve too deeply into this, but infants are vulnerable to infections – this is why infant mortality has always been high. It still is today, and 6 months of age is still the canonical age when the danger lessens:

Globally, approximately 4,000,000 children less than 6 months of age die each year at a rate of 450 deaths per hour. In addition, high hospitalization costs for infected infants are incurred in the United States with an annual estimated cost of $690,000,000.

Formula feeding definitely escalates the risk:

In the United States, more than 40% of all infant hospitalizations are attributable to infectious disease … Diarrhoeal diseases and digestive tract infections are the most common infectious diseases in infants….

Breast feeding has been shown to have a number of beneficial effects in infants, including protection against infectious and allergic diseases. [3]

In this study, 41% of formula-fed infants developed infections between ages 5 and 8 months. [3]

A study from Brazil [4] shows that breastfeeding makes a huge difference in infant mortality:

In a population-based case-control study of infant mortality in two urban areas of southern Brazil, the type of milk in an infant’s diet was found to be an important risk factor for deaths from diarrhoeal and respiratory infections. Compared with infants who were breast-fed with no milk supplements, and after adjusting for confounding variables, those completely weaned had 14.2 and 3.6 times the risk of death from diarrhoea and respiratory infections, respectively. Part-weaning was associated with corresponding relative risks (RR) of 4.2 and 1.6. [4]

Now, deficient serum cholesterol is not the sole factor accounting for higher mortality in formula fed babies. But it is a contributing factor.


If serum cholesterol is healthiest below 160 mg/dl, then formula fed babies have excellent blood lipids despite a high disease and mortality rate, but breastfed babies are already in trouble at age one month and are suffering a shocking dyslipidemia at age six months, despite excellent health.

I think that’s absurd. A more logical interpretation of the evidence is this.

Healthy babies achieve serum cholesterol levels around the adult norm of 200 mg/dl by age six months.

Serum cholesterol levels below 190 mg/dl or so indicate immune suppression and increased risk of infectious disease – whatever the age of the human in question. Formula fed babies are immune suppressed for an extended period – well beyond the six month period of a healthy breastfed baby.

There are multiple causes of low serum cholesterol. A high infectious burden is one; never having eaten is another; a lipid-deficient diet is a third. But there is no evidence I am aware of suggesting that low serum cholesterol is a desirable condition.


[1] Mishkel MA. Neonatal plasma lipids as measured in cord blood. Can Med Assoc J. 1974 Oct 19; 111(8):775-80.

[2] Isomura H et al. Type of milk feeding affects hematological parameters and serum lipid profile in Japanese infants. Pediatr Int. 2011 Mar 21.

[3] Picaud JC et al. Incidence of infectious diseases in infants fed follow-on formula containing synbiotics: an observational study. Acta Paediatr. 2010 Nov;99(11):1695-700.

[4] Victora CG et al. Evidence for protection by breast-feeding against infant deaths from infectious diseases in Brazil. Lancet. 1987 Aug 8;2(8554):319-22.

Blood Lipids and Infectious Disease, Part II

OK, after a diversion into hunter-gatherer lipid profiles I’m back on the original goal of this series: trying to understand why serum cholesterol is protective against infections — and considering whether or under what circumstances that knowledge should affect how we eat.

In part I (Blood Lipids and Infectious Disease, Part I, Jun 21, 2011), we learned that mortality from infectious disease is essentially zero as long as serum cholesterol remains in the physiologically normal range of 200 to 240 mg/dl, and rises precipitously as serum cholesterol falls below 180 mg/dl.

Why is that? In a previous post we found that HDL has important immune functions (HDL and Immunity, April 12, 2011). Today, we’ll look at the immune functions of lipoproteins more generally.

The Logic of Evolution and the Multiple Functions of Lipoproteins

In understanding why these particles have immune functions, it may be helpful to understand the thrust of evolution.

By the time of the Cambrian explosion 530 million years ago, organisms had similar numbers of genes to organisms today, and most of these genes must have been similar in sequence to their modern descendants. We know this because their descendant genes in nearly all modern species are “homologous” and share nucleotide sequences.

So for the last 500 million years, evolution has not been adding genes or even changing genes dramatically. It’s been tweaking a fairly stable genome. And the direction of the tweaking has been toward making the genes interact in a wider and more complex number of ways with the other genes.

The effect is to give every molecule in the body a diversity of functions. Possibly serum lipoprotein particles started out merely as transporters. But they developed new functions. The most important additional functions were roles in immunity.

Because these particles circulate in the blood, and pathogens have to transit the blood in order to cause tissue infections, blood is the natural location for the strongest defenses against pathogens. For hundreds of millions of years, every blood component will have been under selective pressure to develop immune functions.

It’s commonly said that the primary function of LDL and HDL is lipid transport. But this is too narrow a view. Since pathogens are the primary cause of disease, it may be the immune functions of LDL and HDL which account for their significance as biomarkers of health and disease.

The Immune Functions of Lipoproteins

Most of the following discussion will draw from a recent review, “Plasma lipoproteins are important components of the immune system” [1]. References from this paper will be listed in parentheses, eg (1).

Lipoproteins have been shown to:

  1. Prevent bacterial, viral, and parasitic infections.
  2. Detoxify pathogen “die-off” toxins and protect against pathogen toxin-induced tissue damage.
  3. Present pathogen “die-off” toxins to the immune system to trigger antibody formation.

Detoxification and Toxin Defense

When a pathogen dies, it typically fragments and releases compounds which are toxic to humans. Such “die-off” toxins include lipopolysaccharides (LPS) and lipooligosaccharides (LOS) from Gram-negative bacteria, lipoteichoic acid (LTA) from Gram-positive bacteria, fungal cell wall components, and so on.

During infection, the number of such circulating toxins can be vastly larger than the number of pathogens. Such toxins can do a great deal of harm, and often account for most of the ill effects of disease. Medical researchers studying the often-fatal condition of sepsis commonly induce nearly all the characteristics of sepsis in animals merely by injecting LPS.

VLDL, LDL, lipoprotein(a) and HDL can all detoxify LPS and LTA; HDL is the most potent (2, 4, 5). Injecting reconstituted HDL (rHDL) into humans relieves endotoxemia (6) and LPS-induced inflammation in cirrhosis patients (7). Both LDL and HDL detoxify E. coli LPS (35).

LDL binds and inactivates some toxins, including Staphylococcus aureus ?-toxin (8), Yersinia pestis topH6-Ag (30). (Methicillin-resistant S. aureus, or MRSA, is an increasing cause of death in hospitals, and last year claimed my next-door neighbor. See The FDA Is On The Side of the Microbes, Aug 11, 2010).

LDL probably works against many other toxins too, since rats with low LDL have higher mortality when infected, but the mortality can be lessened with injections of human LDL (9). Injections of LDL prevent lethality in Vibrio vulnificus infections of mice (34).

In mice with the LDL receptor knocked out, LDL concentrations in blood are higher and there is enhanced immunity to Klebsiella pneumoniae (27) and Salmonella typhimurium (29). If the gene for apoE, a protein found in IDL which upregulates VLDL levels, is knocked out, mice become more susceptible to infection, so it appears that apoE also has immune functions (28). Mice lacking apoE are susceptible to Listeria monocytogenes (32) and Mycobacterium tuberculosis (33).

Lipoproteins may be even more important against viruses. HDL has a broad antiviral activity (18-20), and can prevent many virus species including influenza and hepatitis C from entering cells. VLDL and LDL have specific activity against certain types of virus including togaviruses and rhabdoviruses (3). Trypanosoma brucei, the parasite that causes sleeping sickness, does not always cause disease in humans because a subspecies can be destroyed by a subfraction of HDL particles which include haptoglobin-related protein and apolipoprotein L-I (10).

The role of oxLDL

Evolution has a way of turning lemons into lemonade, and fragile molecules into sensors. In the book we discuss how the body uses fragile polyunsaturated fats as signaling molecules, exploiting their proclivity to oxidize. Something similar happens with LDL.

LDL particles are fragile and easily oxidized. The body uses them as a sensor of infections, and as signaling molecules that control the response to infections.

For instance, LPS (an endotoxin) induces neutrophils to adhere to endothelial cells, promoting vascular inflammation. LPS also oxidizes LDL, creating a compound called oxPAPC which inhibits neutrophil adhesion to endothelial cells, thereby limiting the inflammatory response (12). Minimally oxidized LDL detoxifies LPS (13).

OxLDL is taken in not by the LDL receptor, but by receptors on immune cells called macrophages. When macrophages take up oxLDL they upregulate their scavenger receptors (classes A and E) by which they phagocytose (eat) bacteria and clear endotoxins (39). It has been shown that infection causes an increase in oxidation of LDL and that the resulting oxLDL promotes phagocytosis by macrophages of the specific pathogens which oxidized the LDL (42).

This may explain why atherosclerotic lesions contain large amounts of bacterial and viral DNA. Macrophages in these lesions have been stimulated by oxLDL to scavenge bacteria and viruses from the blood.

OxLDL stimulates antibody formation, including antibodies against phosphorylcholine (PC), a compound found on a wide range of pathogens including bacteria, parasites, and fungi (45-49). Anti-PC antibodies help to prevent upper airway infections (50-53).

It is thought that oxidation of LDL is an important part of the host defense to infections. OxLDL inhibits cell entry of hepatitis C (59) and Plasmodium sporozite (60).

The role of Lp(a)

Lp(a) is essentially an LDL particle with an extra apo(a) molecule bound to the apoB100 molecule by a disulfide bridge.

Some insight into the immune functions of Lp(a) developed after considering the role of plasminogen. Many pathogens recruit human plasminogen and use it to penetrate tissue barriers, enabling them to invade tissue (70, 71, 72). For instance, group A streptococcus releases an enzyme called streptokinase that activates human plasminogen and promotes invasion (73). Lp(a) has anti-fibrinolytic activity and recruits plasminogen itself, reducing availability for pathogens. For instance, Lp(a) blocks streptokinase activity (75), inhibits Staphylococcus aureus activation of plasminogen.

Moreover, Lp(a) inhibits the inflammatory response to LPS. As there is great variation in Lp(a) levels among individuals (76), this may account for variability in inflammatory response to infections.

The Exception: Candida

HDL may promote fungal infections. A recent study found that infusion of reconstituted HDL enhances the growth of Candida (25).

LDL also seems to promote fungal infections. In LDL receptor knockout mice, which have high levels of LDL, there is decreased resistance to Candida (37, 38).

OxLDL also loses its normal anti-infective role against Candida. Worse, it inhibits production of antibodies against Candida albicans (63), thus actually hurting anti-fungal immunity.

Candida is an unusual pathogen that is unusually well-adapted to living in the human body. It has learned to turn an important part of human immune defense to its own advantage.


High serum cholesterol protects against a host of bacterial and viral infections and some parasites, but increases risk for Candida fungal infections.

Related Posts

Other posts in this series include:


[1] Han R. Plasma lipoproteins are important components of the immune system. Microbiol Immunol. 2010 Apr;54(4):246-53.

Serum Cholesterol Among Hunter-Gatherers: Conclusion

So far we’ve looked at serum cholesterol among Eskimos/Inuit (Serum Cholesterol Among the Eskimos and Inuit, July 1, 2011) and !Kung San bushmen (Serum Cholesterol Among African Hunter-Gatherers, July 5, 2011). The Inuit, who live in the Arctic and eat a high-fat low-carb diet, generally had serum TC over 200 mg/dl unless parasitic diseases were common and life expectancy was short. The !Kung San, who live in sub-Saharan Africa and eat more carbs, were below 160 mg/dl and ridden with parasitic diseases and short life expectancy.

I thought I’d wrap up the hunter-gatherer cholesterol series by looking at some tropical populations outside Africa. These peoples may help us evaluate the merit of several explanations that have been put forth for variations in serum cholesterol:

  • Genetic differences. Africans tend to have lower cholesterol than non-Africans, wherever they live. Is the difference genetic? Chris Masterjohn believes genetic differences might account for up to a 30 mg/dl difference in TC. Emily Deans suggests LDL receptor variants are the most important alleles.
  • Dietary differences such as fat intake. For decades it was said that higher fat diets produce higher TC, and this was the favored explanation for variations in serum cholesterol. However, when these ideas were tested in clinical trials, diet-induced changes in TC were inconsistent.
  • Infectious disease burden. Eukaryotic pathogens such as protozoa, worms, and fungi – ie, pathogens that have mitochondria and therefore can metabolize fat and ketones – are often able to take up human lipoproteins from blood and use their fats and cholesterol for their own purposes. This tends to lead to low TC in people with a high burden of parasites. Is parasite burden the key to hunter-gatherer cholesterol levels?

We started this detour (see Did Hunter-Gatherers Have Low Serum Cholesterol?, June 28, 2011) to evaluate the claims of S. Boyd Eaton, Loren Cordain, and collaborators [1], [2], [3], [30]. Their papers tended to promote the following syllogism:

  1. Diet determines TC.
  2. Low TC is healthy.
  3. Hunter-gatherers had low TC.
  4. Therefore, hunter-gatherer diets are healthy.

So to conclude today’s post, I’ll review: Which of these four theses is supported by the data?

Australian Aborigines

There are a fairly large number of papers on cholesterol levels in Australian aborigines. Unfortunately, the vast majority are from journals, such as the Medical Journal of Australia and the Australian and New Zealand Journal of Medicine, to which I don’t have electronic access.

Therefore I’ll just cite one, a 1957 paper from Schwartz et al in the Australian Journal of Experimental Biology and Medical Science. [31]

This paper looked at aborigines from central Australia. Occupying marginal territory, they were still living a hunter-gatherer lifestyle. But there weren’t many animal foods available, nor seafoods:

The animal fat intake of the Central Australian aborigines from the Haast’s Bluff region involved in this present study is decidedly low when compared with the average intake of white Australians. This low intake of fat results both from a scarcity of fat itself, and also from demands made upon available supplies by native customs. It is likely that the males eat more animal fat than the females, because of their readier access to it after hunting, but the difference is probably small. Wichitty grubs (larvae of several species of Xyleutes moths) are an important source of fat for both women and children, however. Somewhat less than 10 p.c. of the calories in the aboriginal diet is derived from animal fat, i.e. less than one-third of the calories so derived in the white Australian diet (N. B. Tindale, personal communication). [31]

To get even 10% of calories from animal fat, they had to eat a lot of grubs.

So did this low-fat diet produce high or low cholesterol?

Serum cholesterol: … There is no significant difference between the mean values for aboriginal male (217.0 mg/dl) and aboriginal female (207.9 mg/dl). [31]

This is right in line with the levels in Eskimos and Inuit, and in the minimum mortality range of 200 to 240 mg/dl.

Australian aborigines were said to have a mean TC of 146 mg/dl (male) and 132 mg/dl (female) in Eaton et al [1]. Australian aborigines were deleted from the list of hunter-gatherers with low cholesterol in a subsequent Cordain et al paper [2]. I don’t know why this was, but I can say that at least some Australian aboriginal populations had TC over 200 mg/dl.


Kitavans preserved their hunter-gatherer lifestyle until recently, and Staffan Lindeberg and colleagues were able to assess cholesterol levels using modern procedures. They reported serum total cholesterol in men of 4.7 mmol/l (182 mg/dl) and in women of 6.1 mmol/l (236 mg/dl), for a male-female average of 5.4 mmol/l (209 mg/dl). [32]

Health in Kitava was generally good, although life expectancy was only 45 years [33]. Causes of death were infectious disease (notably malaria) and accidents such as drowning and falling from coconut trees.

So we have another tropical, high-carb population with normal (200 to 240 mg/dl) serum cholesterol.

New Zealand Maoris

New Zealand Maoris are probably genetically similar to Australian aborigines and Kitavans. I didn’t survey the literature on New Zealand Maoris. However, I did come across one paper [35] that led me to an interesting 1980 study of Maoris by Dr Robert Beaglehole [36].

The study was quite simple:

The relation between serum cholesterol concentration and mortality was studied prospectively over 11 years in 630 New Zealand Maoris aged 25-74. Serum cholesterol concentration was measured at initial examination in 1962-3 in 94% of the subjects and whether each was dead or alive was determined in 1974. The causes of death were divided into three categories: cancer, cardiovascular disease, and “other.” [36]

Mean serum cholesterol was 5.50 mmol/l (213 mg/dl) among women, 5.82 mmol/l (225 mg/dl) among men, for a population mean of 219 mg/dl.

Dr Beaglehole found that mortality increased as serum cholesterol decreased. Mortality was 40% to 70% higher in Maoris with TC of 160 mg/dl than in Maoris with TC of 260 mg/dl.

The association with cancer mortality was strongest: cancer mortality was 9.6% among the low-TC group (TC < 5.1 mmol/l = 197 mg/dl), 5.8% among the medium-TC group, and 3.5% among the high-TC group (TC > 5.8 mmol/l = 224 mg/dl).

West Malaysian aborigines

Just to balance the above studies I looked for a paper showing low serum cholesterol in an aboriginal population. I found a 1972 paper by Burns-Cox et al studying aborigines in West Malaysia. [37]

Like other traditional populations living active lives, these aborigines were lean and free of heart disease. They ate a high-carb diet:

Coronary heart disease has never been found in Malaysian aborigines. We report the position regarding some of the risk factors usually associated with coronary heart disease in 73 adult aborigine men.

They lived a physically active life on a diet largely of unrefined carbohydrate in the jungles of central West Malaysia. None was obese and blood pressures remained low at all ages. [37]

Their serum cholesterol levels were low – 141 to 156 mg/dl:

While the mean serum cholesterols were low, varying between 141 and 156 mg/100 ml at different ages, the mean fasting serum triglyceride levels of 135 to 164 mg/100 ml were comparable with those found in the West. This may have been due to their high carbohydrate intake. [37]

They were mostly healthy – except that they were infested with intestinal worms and malaria:

The aborigines are thin, extremely fit physically, and for many centuries have lived in the dense hilly jungles of central West Malaysia. They have a high rate of infestation with intestinal worms and malaria but appear well nourished. Their diet consists chiefly of hand-milled rice as a staple, supplemented with cassava, millet, maize, fish, and fruit, nearly all of which they grow or gather themselves. Dairy produce is taken only in very small quantities in the form of reconstituted powdered milk and it is the large volume of starchy foods which accounts for their bulky diet. [37]

Once again, we find that low serum cholesterol is associated with a high burden of eukaryotic pathogens.

Another feature that this population shares with the !Kung San is small stature. Mean averaged 5’1” (155 cm) in height and averaged 105 lb (48 kg) in weight.


Let’s look at the four parts of the syllogism I’ve attributed to Eaton and Cordain:

Diet determines TC. Wrong. It looks like burden of parasites is the major determinant of serum cholesterol in hunter-gatherers and human populations globally.

Low TC is healthy. Wrong. It is associated with high infectious burden, small stature, high mortality, and short lifespan.

Hunter-gatherers had low TC. Some did, some didn’t. So let’s look at a specific claim, this from the classic Cordain-Eaton paper from 2002, “The paradoxical nature of hunter-gatherer diets: meat-based, yet non-atherogenic” (thanks, Rob!):

Over the past 64 y, anthropological research has consistently demonstrated relatively low serum cholesterol and triaglycerol levels among indigenous populations that derive the majority of their diet from animal products. [30]

Wrong. Anthropological research has not consistently demonstrated low serum cholesterol and triglycerol levels from hunter-gatherers, regardless of whether the primary dietary source was animals (Eskimo/Inuit) or plants (Kitavans, Central Australian aborigines). Rather, those with high parasite burdens had low cholesterol, regardless of diet, and healthy populations without parasites had serum cholesterol over 200 mg/dl regardless of diet.

Therefore, hunter-gatherer diets are healthy. True! Except insofar as dietary practices, such as the Eskimo practice of eating raw intestines from recently killed animals, predisposed them to picking up parasitic infections.

Overall I think the data should dispose us to look toward infectious burden, rather than genetics or diet, as the primary determinant of serum cholesterol among hunter-gatherers. If genetic differences influence mean TC among hunter-gatherer populations, it is probably because of evolutionary adaptations to local pathogens, such as the heavy parasite burden in sub-Saharan Africa.

Related Posts

The posts in this series are:


[1] Eaton SB, Konner M, Shostak M. Stone agers in the fast lane: chronic degenerative diseases in evolutionary perspective. Am J Med. 1988 Apr;84(4):739-49. Full text:

[2] O’Keefe JH Jr, Cordain L, Harris WH, Moe RM, Vogel R. Optimal low-density lipoprotein is 50 to 70 mg/dl: lower is better and physiologically normal. J Am Coll Cardiol. 2004 Jun 2;43(11):2142-6.

[3] Konner M, Eaton SB. Paleolithic nutrition: twenty-five years later. Nutr Clin Pract. 2010 Dec;25(6):594-602. Full text:

[30] Cordain L et al. The paradoxical nature of hunter-gatherer diets: meat-based, yet non-atherogenic. Eur J Clin Nutr. 2002 Mar;56 Suppl 1:S42-52.

[31] Schwartz CJ et al. Serum cholesterol and phospholipid levels of Australian aborigines. Aust J Exp Biol Med Sci. 1957 Oct;35(5):449-56. Full text:

[32] Lindeberg S et al. Cardiovascular risk factors in a Melanesian population apparently free from stroke and ischaemic heart disease: the Kitava study. J Intern Med. 1994 Sep;236(3):331-40.

[33] Lindeberg S et al. Age relations of cardiovascular risk factors in a traditional Melanesian society: the Kitava Study. Am J Clin Nutr. 1997 Oct;66(4):845-52.

[35] Walker AR. Cholesterol and mortality rates. Br Med J. 1980 May 31;280(6227):1320.

[36] Beaglehole R et al. Cholesterol and mortality in New Zealand Maoris. Br Med J. 1980 Feb 2;280(6210):285-7. Free full text:

[37] Burns-Cox CJ et al. Risk factors and the absence of coronary heart disease in aborigines in West Malaysia. Br Heart J. 1972 Sep;34(9):953-8.