Sterol sensitivity: a genetic explanation for success on the Carnivore diet?

Article at a Glance
  • Some people with severe autoimmune conditions have had success on a carnivore diet, which involves eating nothing but red meat.
  • Advocates of the diet have sensitivity to all plant matter, including healthy foods like leafy greens.
  • One possible explanation for success on the carnivore diet is undiagnosed sitosterolemia, a rare genetic condition marked by an inability to clear plant sterols from the body which results in chronic inflammation, joint pain, lipid deposits which form bumps on the skin, and early onset heart disease.

The carnivore diet may be unhealthy to many people:

Why?

The carnivore diet has gotten a lot of ink, but the theory I outline below is a new one. It’s just a theory, but my belief is that many people who have success on the carnivore diet actually have a rare genetic condition, known as sitosterolemia, that prevents their body from excreting the plant sterols they eat.

Instead, these sterols pool and cause inflammation.

What are plant sterols and what is sitosterolemia?

Cholesterol is a form of fat found in animals, and sterols are fats found in plants. Our bodies make cholesterol, but plant sterols can only enter the body through diet. We have to eat them otherwise they won’t show up in the blood. Foods like oats, wheat, beans, nuts and seeds, vegetable oils, and avocado have the highest amounts of sterols, but all plant foods contain some. In other words, the only way to go on a sterol free diet would be to eat nothing but meat.

Sterols are usually touted as healthy because they compete with cholesterol for absorption and have shown an ability to lower heart health markers like LDL-C. In most people, sterols like beta-sitosterol are excreted, they don’t stay in the body. But in others, especially people with mutations in the ABCG8 genes, the sterols hang around and are absorbed into the blood stream. You can see levels of sterol on advanced blood tests like the ones offered by labs like Boston Heart Diagnostics as part of a “cholesterol balance score.” Because humans make 80% of the cholesterol in our bodies, measuring cholesterol won’t do us much good in understanding how much cholesterol we are absorbing, so scientists use plant sterols as a proxy. By measuring sterols, we get an idea of how cholesterol is circulating in the body and how much we absorb. If our sitosterol levels are high, we are an absorber of cholesterol and sterol, or so the thinking goes.

The issue first came on my radar when I noticed high levels of beta-sitosterol in my blood after a recent draw.

I had been eating a diet very high in sterol, which put my levels at 3.9 mg/dl, the highest they’ve been. I know from previous blood draws that 1.8 mg/dl was my lowest, which means I am an absorber of cholesterol. But for people with sitosterolemia, 3.9 mg/dl of sitosterol is nothing. Some people with the condition have triple these amounts and often much more. They have tons and tons of plant sterols circulating in their blood.

Why?

The ABCG8 genes and sterol clearance

Variants in the ABCG8 genes are associated with sitosterolemia. In essence, the ABCG8 genes helps the body get rid of plant sterols and certain “mutations” in the gene cause sterol to hang around where they can do damage.

I know by analyzing my SNPs and labs that I don’t have sitosterolemia, but I do have two SNPs in my ABCG8 genes, which led me to theorize: what if just as urea cycle function fluctuates from person to person, which is part of the reason why certain people feel great on a high protein diet and others feel terrible, sterol clearance fluctuates as well?

Kids born with mutations in genes like CPS1, which govern the body’s ability to break down the ammonia generated by digesting animal protein, get very ill the minute they eat any protein. They just don’t have the enzymes in their body to deal with the ammonia and any levels immediately become toxic.

It’s possible this is also the case for sterol absorption. Some people clear 95% of what they eat, others clear 50%, and perhaps certain people only clear 25% or less. Diminished ABCG8 function causes a rapid build up of sterol, which results in an immediate inflammatory cascade that continues until the sterol is no longer ingested. What other explanation could there be for the most hard core carnivore dieters casting leafy greens in the role of dietary bad guy? Leafy greens contain sterol. For most of us they are healthy, but perhaps for a very small subset of the population, they do damage.

In other words, we all absorb sterol at different rates based on our unique genetic profile, and those with an autoimmune condition, especially that impacts joint health and mood, could be undiagnosed cases of sitosterolemia.

Carnivore dieters have sitosterolemia symptoms

Now, there are some arguments against this theory, one of which is that those with sitosterolemia tend to develop heart disease very early in life, sometimes as early as childhood, and the most famous carnivore dieters don’t seem to fall into this category. However, sitosterolemia is said to be under diagnosed (presumably because 99.99% of people never have their sterol levels measured) and if you take a look at Mikhaila Peterson’s blog (Mikhaila is perhaps the best known carnivore dieter) many of the symptoms she lists are consistent with a sterol absorption problem. She mentions “painful bumps” on her skin and debilitating joint pain that caused her to suffer through multiple joint replacements.

Could the “bumps” Mikhaila talks about be xanthomas, which are lipid deposits sitosterolemia patients often have?

Those who are over absorbing sterol also have major problems with joints as the result of sterol deposits actually accumulating in the joints.

To quote the NIH article on sitosterolemia:

Some people with sitosterolemia develop small yellowish growths called xanthomas beginning in childhood. Xanthomas consist of accumulated lipids and may be located anywhere on or just under the skin, typically on the heels, knees, elbows, and buttocks. They may also occur in the bands that connect muscles to bones (tendons), including tendons of the hand and the tendon that connects the heel of the foot to the calf muscles (the Achilles tendon). Large xanthomas can cause pain, difficulty with movement, and cosmetic problems.

The interesting thing about sitosterolemia is that patients who have it often have normal cholesterol levels.

In closing, I still think the carnivore diet is a bad idea for most people. Mikhaila Peterson is very brave to share her story, and you can’t help but admire her quest to find out what works for her body. Having said that, advocating for a carnivore diet writ large and encouraging people to try it, is in my view, irresponsible because, whether the issue is sitosterolemia or not, most people won’t have the extreme reaction to eating plants that the carnivore dieters have.

Testing for sterol absorption

If you want to have your sterol levels tested, Boston Heart Diagnostics is a great lab, but you’ll need to call them to ask which, if any, doctors in your area offer their tests.

Below, I have also included a list of the SNPs associated with sitosterolemia. If you have your 23andme or Ancestry file, these SNPs will be included.

Gene rsID Number
ABCG5 rs119479067
ABCG5 rs119480069
ABCG5 rs119480070
ABCG5 rs3806471
ABCG5 rs387906912
ABCG5 rs6720173
ABCG5 rs6756629
ABCG8 rs137852987
ABCG8 rs137852988
ABCG8 rs137852989
ABCG8 rs137852990
ABCG8 rs137852991
ABCG8 rs137852992
ABCG8 rs137852993
ABCG8 rs137854891
ABCG8 rs199689137
ABCG8 rs4148211
ABCG8 rs4148217
ABCG8 rs6544718

 

ABCG8

Protein:

ATP Binding Cassette SGM8

SNP ID:
  • T322+431C
  • G55C

 

ATP Binding Cassette SGM8 (ABCG8) is a transporter protein which controls the absorption and excretion of cholesterol and other lipids in the gut, and is encoded for by the ABCG8 gene 1.

ABCG8 is expressed in the liver, colon and intestine and acts as a half-transporter protein, meaning it preferentially shuttles molecules in one direction. In the intestine it functions to limit the absorption of cholesterol and other fats from dietary intake. However, it then promotes the secretion of the majority of cholesterols and other fats which do manage to get absorbed into the bile which is then excreted from the body.

There are two SNPs in ABCG8 that are associated with differing poor health outcomes; rs6544713 or T322+431C is associated with an increased cardiovascular risk, whereas rs11887534 or G55C is associated with an increased risk of developing gallstones.

T322+431C

rsID Number Major Allele Minor Allele Minor Allele Frequency (%)
rs6544713 C T 17

Risk Description

The risk ‘T’ allele of T322+431C in the ABCG8 gene was one of several SNPs that were flagged as being associated with an increased risk of developing coronary heart disease 2. The ‘T’ allele was associated with increased levels of LDL which are themselves known to be associated with an increased cardiovascular risk 3.

The authors of the study do not describe a mechanism as to how the ‘T’ allele of T322+431C contributes to an increased level of LDL detected in the blood. However, based on the known function of ABCG8 it is possible to hypothesise that the ‘T’ allele leads to a reduction in ABCG8 function promoting greater uptake of cholesterol and other lipids from the diet, and a reduced secretion of these lipids into the bile.

What to do :

Take in the following:

Oleic acid Oleic acid, sometimes called omega-9 fatty acid, is a major component of olive oil and is thought to be a major driver of the beneficial cardiovascular effects associated with the so called Mediterranean diet 4.

Oleic acid supplementation, or the inclusion of olive oil in the diet, may benefit those carrying the the risk ‘T’ allele of T322+431C, which is associated with increased LDL cholesterol 5

Tangerine Oil Tangeretin Tangeretin a flavone compound which is isolated from tangerine oil. Able to reduce both the levels of LDL cholesterol and total blood lipids 6.

Supplementation may therefore benefit those carrying the the risk ‘T’ allele of T322+431C.

https://www.ncbi.nlm.nih.gov/pubmed/11099417

https://www.ncbi.nlm.nih.gov/pubmed/23202125

https://www.ncbi.nlm.nih.gov/pubmed/28300080

https://www.ncbi.nlm.nih.gov/pubmed/18772370

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC54010

https://www.ncbi.nlm.nih.gov/pubmed/17626266

https://www.ncbi.nlm.nih.gov/pubmed/17098593

https://www.ncbi.nlm.nih.gov/pubmed/15175352

https://www.ncbi.nlm.nih.gov/pubmed/16844493

https://www.ncbi.nlm.nih.gov/pubmed/9288141

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2763865/

Sitosterolemia, Hypercholesterolemia, and Coronary Artery Disease.

Serum sitosterol has been shown as a surrogate marker of cholesterol absorption.Accordingly, serum sitosterol measurements
could be used not only for the clinical diagnosis of sitosterolemia but also for the prediction of ezetimibe efficacy. It has been shown that some patients with sitosterolemia
suffer from hematologic abnormalities, including abnormal erythrocyte shape, thrombocytopenia, and arthritis.

Dayspring TD, Varvel SA, Ghaedi L, Thiselton DL, Bruton
J, McConnell JP. Biomarkers of cholesterol homeostasis
in a clinical laboratory database sample comprising
667,718 patients. J Clin Lipidol. 2015; 9: 807-881

___________________________________

G55C

rsID Number Major Allele Minor Allele Minor Allele Frequency (%) Major Amino Acid Minor Amino Acid
rs11887534 G C 5 Asp Asn

Risk Description

The ‘C’ allele of G55C in the ABCG8 gene is strongly associated with an increased risk of developing gallstones. Those carrying one copy of the ‘C’ allele were at twice the risk, whereas those carrying two copies of the ‘C’ allele were at seven times risk 6.

It is proposed that the risk ‘C’ allele of G55C is actually a gain of function SNP. Decreased levels of cholesterol and LDL cholesterol are observed in the blood of those carrying the risk ‘C’ allele 7; whereas the cholesterol content of their bile was increased 8. Together, these point towards an increased secretion of cholesterol into the bile, which then leads to the formation of gallstones 9.

Indirect Nutrients:*

Ingredient Active Ingredient Effect
Iron A lack of dietary iron has been associated with cholesterol gallstone formation 10. Therefore, iron supplementation may benefit those carrying the risk ‘C’ allele of G55C which is associated with an increased risk of cholesterol driven gallstone formation.
Vitamin C Ascorbic Acid Supplementation with vitamin C has been shown to protect against the formation of gallstones 11. Therefore, carriers of the risk ‘C’ allele of G55C may benefit from increasing dietary vitamin C intake or vitamin C supplementation.

 

 

CPS1

Protein:

Carbamoyl phosphate synthetase I

SNP ID:
  • C4235A, T1405N

 

Carbamoyl phosphate synthetase I (CPS1) is a protein located in the mitochondria which is involved in the clearance of ammonia formed during the breakdown of proteins and is encoded for by the CPS1 gene. CPS1 is a key driver of protein and nitrogen metabolism and the clearance of the resulting ammonia. Ammonia enters the mitochondria via glutamine or glutamate 1. CPS1 cleaves this ammonia and adds it to a bicarbonate molecule along with another molecule to form carbamoyl phosphate. Carbamoyl phosphate the leaves the mitochondria and enters the urea cycle for subsequent excretion from the body 2.

See also: Can your body handle a high protein diet? The answer may be genetic 

Carbamoyl phosphate synthetase I deficiency is a severe clinical loss of CPS1 activity which results in the accumulation of ammonia in the blood, which results in severe neurological issues 3. Several SNPs have demonstrated an association with this severe clinical disorder, however those affected will have been identified based on symptoms evident at birth.

There is however one SNP which is associated with altered, but not a complete loss of, CPS1 activity C4235A (T1405N) or rs1047891 (sometimes called rs7422339).

C4235A, T1405N

rsID Number Major Allele Minor Allele Minor Allele Frequency (%) Major Amino Acid Minor Amino Acid
rs1047891 C A 33 Thr Asn

 

rsID Number Major Allele Minor Allele Minor Allele Frequency (%) Major Amino Acid Minor Amino Acid
rs1047891 C A 33 Thr Asn

Risk Description

The ‘A’ allele of C4235A in the CPS1 gene is associated with increased homocysteine levels and therefore cardiovascular risk. Alongside this an increase in total cholesterol and low density lipoprotein (LDL) cholesterol has also been observed potentially further increasing cardiovascular risk 4.

Another study demonstrated an alteration in the response of the circulatory system to nitric oxide (NO). NO is a vasodilator which is used to alter the size of blood vessels and thus modulate blood pressure. Those carrying the risk ‘A’ allele displayed a reduced responsiveness to NO suggesting they may be at risk of increased risk of high blood pressure, an effect which was increased in those carrying two ‘A’ alleles 5.

The authors initially hypothesized that this effect was due to reduced enzyme activity. However, this effect was not confirmed upon investigation with the authors therefore suggesting that CPS1 may be acting directly on the circulatory system, independently of NO activity. As such this effect requires further study.

Indirect Nutrients:*

Ingredient Active Ingredient Effect
Nattō Nattokinase Nattokinase is an enzyme which is extracted and purified from a Japanese food called nattō, derived from fermented soybeans. Nattokinase is secreted by the bacteria involved in the fermentation process and has a very strong ability to break down fibrin blood clots 6. A beneficial effect on blood pressure 7, and general cardiovascular health has been described 8. Therefore, supplementation may benefit those carrying the risk ‘A’ allele of C4235A, who may be at increased risk of cardiovascular risk and increased blood pressure.
Bergamot Oil Melitidin and Brutieridin Bergamot orange is a sour citrus fruit similar in size to an orange which was originally grown in areas bordering the Mediterranean. Bergamot oranges were frequently processed into oil for a variety of cosmetic reasons. However, more recently positive health effects have been described for two flavone molecules found only in bergamot oranges; melitidin and brutieridin. Both of these flavones exhibit strong statin (blood pressure lowering) 9 like properties, and also lower lipids present in the blood 10, without a lot of the side affects associated with statin use.

As such supplementation may benefit those carrying the risk ‘A’ allele of C4235A, which is associated with an increased cardiovascular risk and elevated blood pressure as well as an altered blood lipid profile.

Vitamin B6 Pyridoxal phosphate Cystathionine β synthase (CBS) and cystathionine γ ligase are key enzymes involved in the conversion of the harmful homocysteine into the less harmful cysteine. Both enzymes use vitamin B6 as a cofactor, and in the absence of vitamin B6 the activity of both enzymes is reduced. Therefore, supplementation with vitamin B6 may aid in the conversion of homocysteine into cysteine 1112. Therefore, reducing the cardiovascular risk for those carrying the ‘A’ allele of C4235A.
Vitamin B12 Methylcobalamin Vitamin B12 is a co-factor for methionine synthase (MS), which converts the harmful homocysteine into the less harmful methionine. Vitamin B12 binds with MS and allows it to function optimally, therefore when present in low levels MS activity is reduced. This activity accounts for approximately half of the processing of homocysteine into methionine.

Supplementation with B12 will aid the activity of MS which may help reduce homocysteine levels 1314. Supplementation may therefore prove beneficial to those with the risk ‘A’ allele of C4235A who display elevated homocysteine levels.

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