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:
- Prevent bacterial, viral, and parasitic infections.
- Detoxify pathogen “die-off” toxins and protect against pathogen toxin-induced tissue damage.
- 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.
Conclusion
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:
- HDL and Immunity, April 12, 2011
- HDL: Higher is Good, But is Highest Best?, April 14, 2011
- How to Raise HDL, April 20, 2011
- Blood Lipids and Infectious Disease, Part I, June 21, 2011
- Blood Lipids and Infectious Disease, Part II, July 12, 2011
References
[1] Han R. Plasma lipoproteins are important components of the immune system. Microbiol Immunol. 2010 Apr;54(4):246-53. http://pmid.us/20377753.
via this link:
Fascinating stuff, Paul. so much to take in and look into that I don’t have much more to say. Great job. This immune function of lipoproteins needs to be addressed more in the popular press.
Hi Stipetic,
Yes, this is sort of dry, but it’s foundational for thinking about different kinds of infections – and especially for my upcoming Candida series.
This is one factor in why Candida infections are so common among low-carb dieters. Low-carb high-fat diets raise serum cholesterol and HDL, which is mostly good, but benefits Candida. I think we’ll find that the diseases low-carb Paleo dieters get are totally different from the mainstream, thanks to different pathogen profiles. It will take a while for medicine to catch up.
just curious about the definition of ” physiologically normal” total cholesterol numbers being 200-240. Why do most MDs believe under 200 is ideal? And in your opinion, what does it mean if TC numbers are in the 240-300 range?
Hi Emily,
I call that range “physiologically normal” because all healthy populations (except possibly for Africans, who might be a trifle lower) seem to fall within it; and because it is the range in which mortality is minimized.
Most MDs believe under 200 is ideal due to an undue focus on cardiovascular disease. Cardiovascular disease risk is reduced by calorie restriction and lipid deficiencies. However, other causes of death are elevated by those same practices.
Unfortunately, medicine has tended to overlook the immune functions of lipoproteins and focus on their lipid transport functions and oxidative potential, which were relevant to the leading theories of CVD causation. This mistake has a complex history, but it shows how easy it is to go astray in biology, and how narrow is the focus of our current over-specialized research system.
What does it mean if TC is over 240? Great question, but a difficult one to answer comprehensively. In most Americans it indicates diabetes or pre-diabetes, hypertension, and related pathologies. More generally it is suggestive of vascular dysfunction and excessive oxidative stress in vessels. This can arise for various reasons, most of which have not yet been studied. I’ve done a blog post on this (http://perfecthealthdiet.com/?p=2536 and http://perfecthealthdiet.com/?p=2547) and will re-visit the topic later.
Best, Paul
Thank you so much for this provocative take on LDL/HDL. My husband went off statins, in part, because of your great book and this blog with all the research citations….he is an ex-scientist. Last month, about 6 months off statins and probably too LC, he came down with very bad Candida infection of the throat/esophogous. Needed treatment with Nystatin…did nothing…then Diflucan…which worked. He had to fess up to his doctor that he went off statins and I was waiting for the lecture re: statins protecting against Candida. I did find this paper: http://www.medscape.com/viewarticle/721004. The doctor at first said an infection like that is usually indicative of something serious (cancer, diabetes, AIDS)but when it cleared up, he just said “Oh well, let’s move on here, nothing to see”. We have since upped his carbs, trying to cut down his daily glass or two of wine and very much looking forward to your upcoming Candida series. Hopefully there are better options than Statins for controlling Candida. Again thanks so much for this great blog.
Hi Deidre,
Great story … all too common. I’m sure a lot of low-carb Paleo dieters have developed candidiasis.
Your husband is smart, that was good to increase carbs and limit wine to a glass a day.
Your doctor’s list should be “cancer, diabetes, AIDS, low-carb diet.”
Very interesting link, thank you. Looks like statins may also reduce ergosterol synthesis in fungi, just like Diflucan. I do believe there are better options than statins for controlling Candida, but it looks like statins may not be a bad anti-Candida therapy! In immunocompromised patients Candidiasis can be fatal, and there are few drugs, and resistance develops, so it’s good to have another therapy in the arsenal.
Best, Paul
Paul, a bit off topic, but how does Candida ‘spread’? I don’t think of an infection as being contagious, but can the pathogens be shared via mouth biofilms?
Hi Nick,
There are basically three leading pathways.
The traditional, evolutionarily old pathway is via food. Humans eat meat from an infected animal and pick up the pathogen that way. Scavenging can move the Candida down the food chain.
However, Candida is more and more becoming a human-only pathogen that is better adapted to humans, less well adapted to animals, and needs to spread human-to-human. The leading vector for these new strains is via saliva, semen, and vaginal fluids from mouth, vagina, and urinary tract. Deep kisses, oral sex, and sex are the major transmission mechanisms.
Candida also spreads from mother to baby during birth via vaginal contact.
Skin contact is also a possible vector, but probably rare. Blood transfusions could be another vector.
> 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.
Holy crap, this blog blows my mind on a regular basis!
Paul, do you think the body has evolved to downregulate LDL receptors or increase LDL production in response to infections?
I am very much looking forward to future posts on chronic infections (I think I might be struggling with one myself).
Hi Andre,
Yes, subSaharan Africans have somewhat different lipoprotein biology due to their high infectious disease burden with its emphasis on protozoal pathogens like malaria, sleeping sickness, etc.
This may affect serum cholesterol levels a bit. Chris Masterjohn said he’s been collecting evidence for genetic differences in LDL and TC and will have posts on it.
My sense is the between-race genetic differences in TC are small, probably 10 mg/dl, in healthy people (but disease responses may be more exaggerated in different races). Chris thinks they may be larger.
Very interesting stuff Paul. My digestive symtoms got progressively worse on a HFLC diet but slowly improved when I added back in carbs. Can’t wait for your candida series.
Hey Paul,
I have been reading your blog for a while now and received great information so far. I suspect I suffer from Candidasis, but the local doctors here in Southern Germany are hardly equipped to do the necessary tests.
I am 21 years old and have been fighting my chronic depression, heavily coated tongue, congested sebum filled pores all over my face and shoulders and sleeping abnormalities for about 20 months. It all started when I got sick on my journey to become a professional athlete. I trained intensively while being on a low carb diet to cut weight when I was treated with antibiotics over the course of 2 months. Gradually the aforementioned symptoms developed and got worse.
I have been feeling extremely sick for the last 8 months, leaving me unable to complete the most trivial tasks. My libido is barely existant and my athletic performance subpar. Apathy has replaced my sanguine attitude and I feel hideous seeing how every pore in my face is filled with sebum. Yet the doctors say my bloodwork suggests that everything is perfectly fine. Does this sound anything like candida?
greetings Marcel
I second that candida series, I might have a bit of a problem with it. I simply don’t do well with fruit. Starch is fine but too much fruit and I get a bit bloated. It’s not terrible but I would rather be able to eat fruit without that problem. I am eating something like a 40% carb 40% fat, 20% protein diet without a whole lot of coconut fat or butter, just because that seems to feel best. Interesting how I would gravitate towards that when it looks to be good for candida.
Hi Marcel,
Yes, indeed it does.
Antibiotics and low-carb dieting (especially combined with intense exercise which increases glucose utilization) are always likely to cause rapid multiplication of any fungi present in the body.
A white tongue is a classic indicator of Candida, so is acne (caused by circulating toxins – cell wall components), so is reduced athleticism/speed/power (I found this was perhaps my most sensitive indicator of Candida status), muscle stiffness, loss of muscle, vascular dysfunction leading to reduced libido and erectile dysfunction, sleeping abnormalities (again due to circulating toxins).
None of the standard blood tests indicate any change during Candida infections. Candida does affect a totally different set of biomarkers, you can look up talks by Dr Ritchie Shoemaker for a list, but most doctors don’t test any of those.
I don’t think you need diagnostic tests, it sounds very obvious.
The first thing I would do is get a prescription for cholestyramine. This will reduce circulating toxin levels (helping acne, sleep, muscle stiffness, liver health) and reduce serum cholesterol a bit which should help.
You should eat plenty of carbs (600+ calories per day) and avoid extended fasts. Eat breakfast.
Then you need probiotics (bacterial only, no yeast). In addition to gut probiotics you can use oral probiotics like Blis K12.
You need to eat a variety of plant foods. All plants are threatened by fungi and make anti-fungal compounds. Traditional herbs like oregano, thyme, and turmeric are good; olive oil (extra virgin with the olive compounds in it) is good; tomatoes are good; spinach is good; berries are good.
Then you need antifungal medicines. I’ve gotten good results from fluconazole and Chinese medicines.
Best of luck and keep me posted.
Paul
Hi Stabby,
Are you sure it’s Candida? Sounds like fructose malabsorpation. Almost anything can eat fructose, so no clue as to what’s causing bloating. Candida can cause bloating, but it’s not the only way it can happen.
Do you take probiotics?
You might have two problems, one in the small intestine impairing fructose absorption and another dysbiosis in the colon causing bloating. They could be the same or different causes. You might try the oral probiotics as they influence small intestinal flora as much as colonic probiotics do. Polysaccharide digesting enzymes might help break up biofilms and let the probiotics work better.
Best, Paul
I suppose I’m not sure that it’s candida, I just assumed that it was. I’ll certainly give probiotics a go. Would this kind be fine? http://www.renewlife.com/ultimate-flora-critical-care-50-billion.html
Also how long should I take them and should I take any fermentable fiber like inulin along with it? Thanks for the reply.
Your post is timely. I just went in for the annual physical and asked my doc about my right big toe. The nail is slightly discolored now and there is a minor numbness in that part of the foot. In the winter the toenail was almost black, and the front part of the foot felt especially numb at times. He immediately diagnosed it as a fungus and then went on to explain that he didn’t have any magic pills to make it go away . . . only some pharma that might or might not work, albeit at risk of potential serious health risks. (He said most men are fine with letting the body slowly heal itself, but some women insist on treatment . . . they have an important social event coming up where they need to wear an open-toed shoe!)
As I think back on it, in the last half of last year I was eating low-carb paleo, and switched over to PHD, including many of the supplements, in first quarter of this year, and that’s when the toe issue started improving. (Correlation may not be causation, yet my story-line says that PHD had much to do with the improvement.)
The blood tests from my recent physical showed LDL at 141, whereas a year ago they had been at 131. I’m not sure if you’re implying that the fungus infection caused LDL to rise, or if LDL is rising to fight the fungus. I probably just need to read your material better.
The other funny story . . . when the nurse called with the blood test results, she said everything looked good except for Total Cholesterol, which was 226. She said I needed to improve my diet. I did everything I could to keep from bursting out in laughter.
Per your comment to Marcel above, is it OK if I continue to practice a 16-hour autophagic fast daily? (13 hours or so of true fast, then assuage hunger with coconut milk and/or coffee with cream). I’m doing that because it seems to be slowly helping me lose weight. I eat plenty of starchy carbs in the 8-hour eating window.
Also, great blog, great book, many thanks for all the things you’re doing.
Hi Stabby,
Yes, it’s fine. I kind of prefer the Primal Defense (not Ultra) because it has more species, and L. reuteri and B. subtilis and Blis K12 to go with it, but yours is good. Certainly has a good quantity. I tend to think species are more important than number, because they can multiply in the gut if they match your diet. Quantity is important if you have diarrhea or anything acute like that.
I would take them until you’re fully healthy.
I wouldn’t take inulin or other fibers which may benefit pathogens too. Rather, just eat a diversity of plant foods which will give you inulin/fiber and antifungal compounds together.
Best, Paul
Hi Kirk,
I would definitely treat the fungus. The good news is that a black fungus is generally an environmental mold and though they can grow on the skin they tend not to flourish in the body, unless you are immune suppressed.
What I would do is paint your nails regularly with either Povidine iodine (eg Betadine) or antifungal creams (like clotrimazole or terbinafine).
Also, eat relatively more carbs. I think you can stick with the fasts as long as you don’t have systemic symptoms. If it invades the body then you need to optimize everything for fungal defense.
Best, Paul
Sounds good, thanks. What about taking the one with less diversity but supplementing with a bit of dirt from the garden? I was eating dirt for a few days after Emily’s post but then I forgot about it. I guess the initial elation wore off.
Hi Stabby,
Afraid I’m not in the dirt is good camp. Plus, can you believe it, Amazon doesn’t list the microbial contents of its dirt supplements: http://www.amazon.com/Hyponex-Potting-Soil-8-Pound/dp/B000BQK6ES/ref=sr_1_6?ie=UTF8&qid=1310587025&sr=8-6. I never supplement anything that doesn’t tell me the ingredients. Plus, it only got 1 1/2 stars.
These dirt companies need to get their acts together, that kind of thing won’t win them consumers in today’s world.
Dr. Jaminet,
Bravo! albeit a lot of what you’ve written is above my head!
ok. i decide to get your book cause i can’t find a “donate” button.
are you going to discuss more on candida? if it is an exception.
FYI: re. the “standard” 200 mg/dL
in case you have not read this:
Dr. Barry Groves wrote an article about it (from Dr. Mary Enig’s recollection).
http://www.second-opinions.co.uk/enig_chol.html
it seemed they could’ve drawn a line anywhere between 200 & 240 to declared it as “normal”.
the reason the lower end (200) of the normal distribution seemed to be that more people would appear to have “high” TC.
regards,
pam
Hi Pam,
I am going to discuss Candida until everyone is sick of it.
Neat anecdote, unfortunately a plausible one. From the biomedical evidence it’s silly to declare anything in the 200 to 240 range to be not normal. From a political/fundraising perspective, however, there’s no better way to raise money than to medicalize normal health. It can work long enough for the perpetrators to reach retirement.
“I am going to discuss Candida until everyone is sick of it.”
Not so fast! Please present evidence for the role of discussion in the etiology of Candida albicans.
Careful Steve, you don’t want to give me laughing sickness.
Paul,
I am almost certain that my last lingering health issues stem from candida. I have been taking Iosol again, worked up to 4 drops a day and will start Iodoral soon. Sleep has improved somewhat, although I still seem to have very vivid constant dreaming, my dandruff is about 95% gone.. no signs of it until i really scrub my hair when its dry and there will be a few flakes. dry flaky skin areas that were previously infected with folliculitis are healign with the Iosol, my skin is keeping more moist but it stil dries and flakes a bit at times. The big sign to me is my tognue is a bit coated now… this is all really strange to me because a back in February, when dandruff and skin were worse, my tognue was not coated at all and my digestion was amazing. Now, my tognue is coated and my digestion is horrible. I am going like 4 times a day and usually only one of them is a perfect BM, the other 3 are not so good, but not diarreah.
Things that have changed are my diet ratios, a higher carb diet with about 55-60% carbs from tubers and white rice, some fruit, veggies, 25-30% fats and 15-20% protein, sometimes higher. I am eating ALOT mind you, to put on weight, basically force feedining myself. I also dropped all dairy and have been dairy free for abotu 2 1/2 months. It is interesting to me that with kefir, my sleep, digestion, energy and tognue were great but dandruff was bad, now without it, dandruff is great but the others listedma re not good,… not sure what to think about this.
I am thinking a better probiotic is in order. Theralac just doesnt seemt to be cutting it anymore. I was using Ohhiras, which was very good. Have you any thoughts on it? I wil try Primal Defense as epr your recommendation.
My T is definitely up.. morning erections and libido have gone way up, some modest strength improvements in the gym. Body temps are consistant 98.0++. If I go really high in starch I wake up with a perfect 98.6 temperature and tend to sustain it throughout the day.
But alas, digestion is poor, I am falling asleep easier but waking up more frequently then before, and all the above maladies. Not sure whether I should go back to my old ratios and hope that the skin and hormonal improves sustain themselves with more Iodine? Vitamin A from liver and skate liver oil also helps with skin and signs of good T.
Thinking of trialling Fluconazole after seeing postive studies regarding its efficacy in treating sebhorhea. Any tips for it? I also read that you recommend Klorox?
Also, per your fasting comments I will stop fasting and start eating breakfast ASAP upon waking…. I have been doing IF regularly for a long time now and should probably call it quits for a bit. I got so used to not really eating before noon.
Bill, I have very similar problems, and I am eating the exact same way you are, essentially a high-carb PHD, with the goal of gaining weight and improving athletic performance. My dandruff has been consistently bad and I still suffer from constipation. I have seen zero improvements in my skin, and probiotics don’t seem to do anything (maybe I just haven’t found the right ones). Paul, what is your opinion on antifungals like Biocidin? I have a small bottle laying around that was given to me by a naturopath but I haven’t got around to using it.
Robert,
We seem to be eating the same but hacve very opposite reactions! With high carb, everything is better except digestion and tognue for me. Dandruff, skin, etc all improve. I also never had an issue with constiptation but have you tried resistant starch? Whenever I eat some I can almost guarantee a good BM.
Also Robert,
Have you tested thyroid or tried Iodine? While all these areas were good for me without Iodine, but showed further imrpovements with its addition.
Hi Paul,
This is a very good series. You are making a strong case that lipoproteins are involved in the immune defense I think you are missing two things, though, to make the argument from part I complete.
In part I, if I understood you correctly, you argued that people with low cholesterol have greater mortality because their low cholesterol makes them more vulnerable to infection, and that sub-Saharan African hunter-gatherers and certain other hunter-gatherer subgroups had or have low cholesterol because they have a high burden of infectious diseases.
I think to support the latter point, you should show that infection decreases cholesterol levels. In my discussion of statins and Rho activation, I cited a study showing that endotoxin causes a massive upregulation of HMG CoA Reductase in hamsters.
http://www.cholesterol-and-health.com/Rho-Activation.html#2
In that paper, they write the following:
=======================
“LPS and cytokines increase serum triglyceride levels and
VLDL production by stimulating hepatic lipogenesis, suppressing fatty acid oxidation, and increasing reesterification of peripherally derived fatty acids (6, 7).
Several studies have demonstrated that LPS also exerts
profound effects on cholesterol metabolism which
may support increased VLDL production. LPS administration
increases serum cholesterol levels and stimulates
de novo hepatic cholesterol synthesis in mice, rats, and
hamsters (8-10).
========================
Perhaps the effects are different in humans or with different infectious agents, but this would suggest that high infectious burden should increase, not decrease cholesterol.
The other thing that I think is needed to complete the argument is to explain why high infectious burden wouldn’t cause selective pressure for higher cholesterol levels. If low cholesterol increases mortality from infectious diseases, then in populations with high infectious burden the people with the lowest cholesterol should be the most likely to die, leaving behind the people with the highest cholesterol. This seems contrary to the data you reviewed in part I.
By the way, what I meant in my last comment was that I personally have, according to 23andMe, alleles accounting for a ~30 mg/dL drop in cholesterol. I didn’t mean that as an estimate of the heritable difference between populations. My Masai series is delayed a little bit because of work pressures but it’s coming!
Regards,
Chris
Hi Chris,
I’m working my way there. The reduction in LDL levels comes from eukaryotic pathogens, chiefly protozoa. Malaria, schistosomiasis, leishmaniasis, … they all lower TC.
Bacterial and viral infections generally don’t depress TC.
I would expect the results from LPS in mice would also be found in humans. I would expect LPS to upregulate lipoprotein involved in toxin clearance, which all VLDL/IDL/LDL do. It also oxidizes LDL promoting clearance, so LDL may not increase as much as VLDL. LPS toxicity will cause vascular injury leading to cholesterol synthesis upregulation in endothelial cells, also LDL receptor upregulation. It would be natural for hepatic cholesterol synthesis to increase to meet higher body demands. Cholesterol is needed for wound repair and for cellular mobility or proliferation.
There’s no contradiction. More protozoa = greater reduction of TC = greater mortality. It’s not that there is a pre-existing distribution of TC and protozoa are selectively killing the low cholesterol population. No, everyone when healthy has TC of 200 and the protozoa are gradually driving it down and then killing them – or they die of something else after the protozoa have weakened immunity.
The point is, everyone in subSaharan Africa has chronic infections, many of them protozoal, but the burden is higher in some than others. So everyone has depressed cholesterol, some more than others. And the ones with the higher burden are more likely to die. But death isn’t quick. Most people carry the infections for 50 years before dying.
Sorry I misunderstood your previous comment. I think 23andMe may be overestimating the effect of your alleles!
Best, Paul
My clinical experience as a surgeon are completely congruent with CM observations as well. I see cholesterol rise to extremely high levels with infection. The more LPS endotoxin involved the higher the cholesterol level.
Hi Jack,
Thanks, good to hear of your experience. As I noted to Chris, there’s plenty of reason to expect LPS to upregulate cholesterol levels.
Hi Robert,
I think the ingredient list looks OK as long as the doses aren’t too high. Don’t overdo it.
Dandruff is often due to Malassezia and some topical antifungals can work.
You might try cholestyramine and see if it clears your skin symptoms.
Hi Bill,
Not quite sure what to make of your experience, but it seems like addressing the gut with probiotics, enzymes, and maybe antifungals would be logical.
Fluconazole is good, I don’t have any tips other than follow the instructions, and combine it with cholestyramine to clear toxins. “Klorox” I assume is Kolorex brand horopito, which is one among a number of natural antifungals. I’ve switched to Chinese medicine and fluconazole. That works well.
Hi Paul,
Great, I look forward to how this develops. I’m a bit skeptical, though, of the idea that there is no heritable variation in cholesterol on which selection could act. But I’ll let you convince me. 🙂
Chris
Hi Chris,
Didn’t mean to imply that, there’s a lot of heritable variation in lipoproteins, though I think mean TC is fairly well conserved on a population level. In saying it was 200 in all healthy people I was just trying to present a simple model to make the more important influence on variation clear.
Yes, I too get stuck between cholesterol serving immune function and infections lowering cholesterol – I can appreciate that malaria and trypanosomes and whatnot might have a different effect than viruses and bacteria – yet why the drop with dementia when the suspected pathogens are viruses and bacteria? All the pieces are not fitting nice and neatly for me though I imagine a very complex set of factors are at work.
Looking forward to this series as two common means of getting more energy (Lugol’s solution and Methylene Bleu) that seem to help me are very potent anti-fungals.
Brushing teeth with bicarbonate salt also seems to help with my otherwise white coated tongue and constant clogged Eustachian tubes.
“I am going to discuss Candida until everyone is sick of it.”
Yipppeee! thanks Paul. Great topic. All your topics are super informative.
Looking forward to the 23rd for sure.
It seems that some virouses and bacteria can lower cholesterol too! Hepatitis C (pubmed 21692949, 21501354), hepatitis B (8490412), epstein-barr (20594556), brucella (19535817), tuberculosis (19133200, 17217941), dengue hemorragic fever (11915007), to name a few.
About candida: Paul, do you know that nicotinamide (also know as niacinamide), a form of vitamin B3, can help to fight candida? (pubmed 19761490 and 20601951).
Thanks, Mario. Looks like we could spend a lot of time on cholesterol if we chose. That helps answer Emily’s question about dementia.
I did know about nicotinamide. It can also help against some viruses. But it hurts against most bacteria. Not a simple therapy.
Paul,
Fascinating nitty gritty on the roles of cholesterol you got going here. It kinda makes you wonder if cholesterol levels often naturally fluctuate based on functional necessity. So if you have an infection of some sort, it goes up, until the job is ‘done’, and then gradually moves back down when the extra workers are no longer needed in the same way. That might sound elementary and simplistic compared to your study.
Not sure if you’ve seen the thread on my VAP results, but it’s quite interesting, given that I eat a very Paleo diet (about 90%) and steer well clear of vegetables oils and other high O6 foods, grains, and never drink fructose drinks or eat high sugary deserts outside of whole fruit, which lately had included a fair amount of banana usually eaten with heavy cream. My main fructose sources over the past 6 months or so has been banana (1-2 per day), dried black mission figs (3-4 figs per day), some raw honey off and on, usually about 1-2 teaspoons at a time. I also eat blueberries and strawberries fairly regularly but there’s really not much fructose in those. My other main source of carbs is sweet potatoes and white rice. As a knee jerk reaction, I have dropped the bananas completely, and basically only have a dollop of cream in my coffee. Basically right now at least 90% of my carbs come from the starch.
A lot of people have gotten involved in this discussion. I would love to know your take on my numbers and what you would personally do, if anything, if you were me. Whenever you have the time to review the thread, please feel free!
http://paleohacks.com/questions/50347/hack-jack-kronks-vap-test-results#axzz1S61vjkXV
Thanks!
JK
Hi Jack,
It’s a little hard to read the tea leaves there. Your numbers are really not abnormal. They are not ideal in some ways but the variation is not in a pattern that stands out as pathological either.
The most surprising one is the triglyceride number.
Do you have any health problems or signs of infection? History of infection, liver disease, or vascular disease? Health status is essential background knowledge for interpreting these.
Another place to look for clues, if you want to do further investigation, would be personal genotyping like Chris Masterjohn did with 23andMe.
I don’t offhand have a take on those numbers but I will keep an eye out for possible causes of high trigs.
Best, Paul
So if infection lowers cholesterol, and we have more chronic infections as we age, then why does cholesterol go up as we age (except for certain cases), and if death is on the line and higher cholesterol protects us via better immunity, why isn’t higher cholesterol selected for in infection-ridden regions? I get how the whole population is infected etc. Etc but wouldn’t that just make for stronger selection pressure? I love Evolutionary medicine because usually the pieces fall rather nicely into place, but this one is a stumper.
Emily,
I think that the key word here is “chronic”. Infections seems to lower cholesterol during acute infections, not chronic. For example:
http://www.ncbi.nlm.nih.gov/pubmed/21692949
“and if death is on the line and higher cholesterol protects us via better immunity, why isn’t higher cholesterol selected for in infection-ridden regions?”
And how do we know that it didn’t? How do we know if thousands of years ago the cholesterol levels in these regions were not even lower than are now?
Hi Emily,
There are some puzzles here. I’m planning to circle back to the problem of high cholesterol at some future date, after which I hope to have a better handle on the various permutations.
Re your question, I guess I would agree that there has been selection pressure for higher cholesterol, but then I’d ask: which people have been under the strongest pressure?
It’s worth remembering that until a hundred years ago, every part of the world was infection-ridden. Infectious disease mortality was very high in England throughout the middle ages. Historically, the rise of fixed settlements and the domestication of animals were probably the two biggest factors increasing infectious disease rates. They were a great equalizer: where before Africans had probably had a higher disease burden, in the Neolithic Eurasians were exposed to the largest burden. Precisely because of tropical diseases killing livestock, farming and domesticated animals and cities came very late to sub-Saharan Africa.
So who was under the most selective pressure for higher cholesterol? Africans, or the Neolithic and urbanized populations of Eurasia?
Then we have Chris Masterjohn’s point: When Europeans arrived in the Americas, vast numbers of American Indians died from new infectious diseases. If the ones with low serum cholesterol died preferentially, there may have been sudden selection for high cholesterol. Now we only see the descendants of the high cholesterol survivors.
All in all I think it’s not obvious what the evolutionary prediction would be. Maybe pathogens have become globalized and every population has had time to evolve TC to something close to the contemporary optimum.
Mario, my reading of that paper is that chronic hepatitis C infections maintain low cholesterol, but that if acute hep C infections are resolved, the cholesterol returns to a level higher than it was pre-infection.
To me that suggests some sort of lasting alteration in liver function. We know fatty liver disease can raise cholesterol. It may be that scarring / fibrin increase liver cholesterol synthesis and export.
Best, Paul
Hey Paul –
Great stuff. I’ve been following your blog for a while now, and found it incredibly helpful. This series really hits home for me.
I’ve been trying to get a clear diagnosis on an issue I’ve had for the past year or so. I did a VLC stint for about 6 months. Understandibly in this time, I felt incredibly sluggish, and just off. Somewhere in that time, I noticed a lump in my submandibular gland and went to get it checked out. Bloodwork came back and showed iron saturation of 96%, low WBC, low RBC, and enlarged red blood cells. I was referred to hematology/oncology and they suspected hemachromatosis. They didn’t find enough evidence there, and ruled out lymphoma, and referred me back out. I’ve been bounced around between 5-6 specialists and nobody can seem to figure it out. Reading this series, and some of your past entries over along with the comments, makes me think I may have a candida issue and some serious mineral defficiencies. I don’t supplement anything, but I started eating liver but have been scared off a tad from the hemachromatosis issue looming.
Would this explain the symptoms? Here are 2 links to some running lab numbers
[1]: http://paleohacks.com/questions/21446/got-some-lab-results-back-any-suggestions-updated-5-10-11-added-vap-doc-wor#axzz1S7USoPNe
[1]: http://paleohacks.com/questions/47129/iron-overload-and-anemia-with-impaired-kidney-function-hypothyroid-labs-value#axzz1S7USoPNe
Many thanks
Hi Todd,
I’m not qualified to make diagnoses, especially in complex issues like yours.
My general take on these things is that you want to try to optimize diet and nutrition as much as possible, because that will clarify symptoms.
When I was sick and eating a bad diet, a diagnosis was impossible. When I started eating a good diet, some things improved, but everything else clarified, and it became obvious that I had a bacterial infection. Instead of a confused set of symptoms due to a complex of infections, malnutrition, and food toxicities, the symptoms looked more like a “classic” infection.
In your case, for instance, one cause of enlarged red blood cells is vitamin B12 or folate deficiency (http://www.mayoclinic.com/health/macrocytosis/AN01287). B12 deficiency causes pernicious anemia / sluggishness (http://www.medicinenet.com/pernicious_anemia/article.htm). Suppose you had that. Fixing it might remove a few of your symptoms, and make any remaining symptoms fit better into a known diagnostic syndrome.
Now, I don’t know what’s causing your issues, but I think you should try your best to be well nourished. So eat your liver and take vitamin and mineral supplements.
Then, after any nutrient deficiencies are relieved, you can go back for more testing and have a better chance at getting diagnosed.
Best, Paul