The Cholesterol Hypothesis Epic Fail

Medicame This 2015 Japanese study had a few things to say about the idea that high cholesterol causes heart disease, about the so called benefits of low cholesterol, and about cholesterol lowering drugs…and they aren’t particularly complimentary.

Annals of Nutrition & Metabolism 2015;66(suppl 4):1–116

And in fact it isn’t just this one study, and it doesn’t just apply to Japan. The truth of the matter is that the popular belief system, which suggests that high cholesterol is one of the main drivers of cardiovascular disease (and other related metabolic illnesses), and that lowering cholesterol is a big part of the answer, is problematic and misleading, and seems to disregard a large body of scientific evidence.

But this is not to suggest that high levels of cholesterol in the blood, never occur as a result of metabolic health issues, are never associated with an increased risk of susceptibility to illness, and can never be involved in the development and progression of disease. That’s a slightly different issue, and unfortunately without a little discussion about context, yes and no answers are rarely enough to provide a clear picture.

“Cholesterol is a negative risk factor for all-cause mortality…mortality actually goes down with higher total or low density lipoprotein (LDL) cholesterol levels…” (Ann Nutr Metab 2015)

“The theory that the lower the cholesterol levels are, the better is completely wrong in the case of Japan, in fact, the exact opposite is true.” (Ann Nutr Metab 2015)

The truth of the matter is that, no matter where you are from, it’s normal for cholesterol levels to rise under certain conditions or circumstances, and this is not necessarily a bad thing, and it isn’t something to be afraid of per se.

And yet, that is not the same as saying, I never want to bring my cholesterol levels down. Nor is it the same as saying, I always want my cholesterol levels to be high. It’s the way that things work together that matters, and without a look at the big picture, it can be hard to see how something can be both good and bad at the same time. The thing is, it depends on why cholesterol is high or low, and it also depends on what is being compared to what.

From a physiological perspective, cholesterol – alongside glucose – plays a fundamental role in the protection against biochemical stress, as well as protection from degeneration and disease in general.

When a healthy person is exposed to stress, the production of cholesterol – which also happens to be the precursor to the protective ‘anti-stress’ steroid hormones (pregnenolone, progesterone, and DHEA) – increases defensively.

Ongoing exposure to stress (and the cumulative effects of aging), interfere with thyroid metabolism and energy system function, inhibiting the ability of the body to convert cholesterol into the more specialized anti-inflammatory hormones mentioned above, and so it becomes common for circulating cholesterol to rise.

Under these circumstances, cholesterol is still highly protective, however that does not mean that metabolic health is optimal. Unfortunately, it also does not mean that interfering with the production of cholesterol is the right solution.

“Elderly people with high cholesterol levels live longer irrespective of where they live…it seems clear that high cholesterol levels should not be considered unhealthy especially in elderly people. (Ann Nutr Metab 2015)

“Mortality from infection is low in subjects with high cholesterol levels. This is because low density lipoprotein (LDL) and other lipoprotein particles stick to bacteria (and their toxic fragments) and viruses, decreasing their toxicity.” (Ann Nutr Metab 2015)

In fact, there are a number of biologically valid reasons why low cholesterol is not something to aim for, especially when achieved via methods which interfere with the production of cholesterol, rather than methods which decrease cholesterol requirements, or increase conversion of cholesterol into other even more protective substances.

Interfering with cholesterol production, thereby preventing the supply of cholesterol needed for proper metabolic function (including protection from increased levels of metabolic stress), is not a good idea, even if it’s also true that high cholesterol is generally not a sign of optimal health.

Actually, arguably one of the worst things to do when metabolic stress is high and overall function is sub-optimal, is to get in the way of the production of something which exists as a big part of normal function, and which rises to deal with worsening issues, or as a kind of last line of defense.

“One of the biggest contributors to the inverse correlation between the lowest cholesterol levels and the highest all-cause mortality is cancer mortality…” (Ann Nutr Metab 2015)

“Low cholesterol levels constitute a risk factor for stroke mortality, while mid to high cholesterol levels constitute a low risk…” (Ann Nutr Metab 2015)

“Liver disease seems to show the most marked association with cholesterol. Liver cancer incidence, liver cirrhosis mortality, and liver disease mortality have been found to be null in subjects with the highest cholesterol levels…” (Ann Nutr Metab 2015)

The importance of cholesterol, when it comes to proper cellular and energy metabolism function (including protection from inflammation and infection, as well as biochemical stress in general), cannot be overstated. This is why interference with the production and metabolism of cholesterol, has the potential to be involved in the development of so many different metabolic conditions, including cancer and diabetes.

Inhibiting the ability to produce cholesterol with the use of cholesterol lowering drugs (statins), has been shown to have limited effectiveness, and has been demonstrated to have many potentially serious ‘side effects’, including nervous system disorders (peripheral neuropathy, diminished sexual pleasure and memory impairment), serious birth defects, musculoskeletal disorders, as well as liver dysfunction. There is also evidence suggesting that long term statin use promotes cancer, heart disease, diabetes and other serious illnesses.

“There is accumulating evidence for the carcinogenicity of statins….while statins lower cholesterol levels, they do not prevent CHD disease…” (Ann Nutr Metab 2015)

“If liver damage by statins is serious, cholesterol levels may be markedly decreased by a compounding effect, namely, reduced cholesterol synthesis through the primary pharmacological effect of statins and liver damage, which also decreases cholesterol synthesis, as a side effect. And this compounding effect may start a vicious cycle.” (Ann Nutr Metab 2015)

“…Are statins actually effective for preventing coronary heart disease in type 2 diabetes mellitus….the answer is unfortunately ‘No’…In fact, statins deteriorate glucose metabolism and increase…diabetes…” (Ann Nutr Metab 2015)

The polyunsaturated fats (PUFAs), which are also well known to have cholesterol lowering effects, interact with circulating cholesterol in a manner which promotes the oxidation of cholesterol, and oxidized cholesterol is directly involved in the development of inflammation and cardiovascular disease, and other inflammatory illnesses including Alzheimer’s. Of course, this does not mean that cholesterol is the fundamental issue.

Even if statins can to some degree reduce exposure to oxidized cholesterol, it is more logical to limit exposure to the substances which are responsible for the damage to cholesterol, namely PUFAs and some other inflammatory things.

Apart from interfering with the production of cholesterol in the liver, the PUFAs are known to cause damage to the liver, to powerfully suppress thyroid energy metabolism, and to drive chronic and systemic inflammation. Reducing inflammation, has been shown to protect against heart disease, diabetes and cancer. This has been shown to be effective, even whilst cholesterol remains high.

“When…findings on liver disease and cholesterol are seen together, they all point to the fact that high cholesterol levels prevent liver disease.” (Ann Nutr Metab 2015)

“Because the liver is the major organ that synthesizes cholesterol, its dysfunction may reduce the available supply of cholesterol for hepatocyte reconstruction. If cholesterol is abundant in the blood from the beginning of liver disease, secondary damage to the liver due to cholesterol insufficiency might be avoided.” (Ann Nutr Metab 2015)

So things can get a little confusing. Because cholesterol can be high because of stress and interference with thyroid energy systems, and this can be a bad thing in the sense that stress and metabolic suppression leads to inflammation and disease. But it’s also a good thing in the sense that high cholesterol is protective under these circumstances. If however, there is ongoing exposure to PUFAs and other inflammatory things, high cholesterol can itself become part of the problem. Again, that does not mean that the situation would be improved if cholesterol production was brought down, whilst stress and inflammation, and exposure to PUFAs, remains high. In fact this would potentially lead to far worse results.

Lowering stress and inflammation, whilst improving thyroid function, can, on the other hand, lower cholesterol levels (from both less production and increased conversion), and this can be beneficial. The answers are not always clear-cut, which can be a serious problem in a world where black and white, one size fits all simple solutions, are seen as preferable and are heavily promoted. The tunnel vision approach, however, has been known to lead to ‘mistakes’.

“Physicians don’t have enough time to study the cholesterol issue by themselves, leaving them simply to accept the information provided by the pharmaceutical industry…” (Ann Nutr Metab 2015)

“…high cholesterol levels are a good marker of longevity. Unfortunately…doctors try to reduce patients’ cholesterol levels without due consideration of these overall findings.” (Ann Nutr Metab 2015)

“…The biggest mistake made by medical science in the previous century….the cholesterol hypothesis relies on very weak data—and sometimes considerably distorted data….cholesterol plays a very positive role in health.” (Ann Nutr Metab 2015)

“We believe the answer is very simple: for the side defending this so-called cholesterol theory, the amount of money at stake is too much to lose the fight…” (Ann Nutr Metab 2015)

I’m not a doctor or a scientist, and none of this is intended as health or medical advice, but it does seem clear that doctors have little choice but to accept the dominant view, and the dominant view is not always the right view. Science continues to provide conflicting results and opinions, but the more biology you read, the clearer it seems that the protective role of cholesterol is being largely ignored, and the so called causative role of high cholesterol in the promotion of heart disease, is exaggerated at best.

“The fact that the effects of cholesterol on CHD mortality decrease with age strongly suggests that high cholesterol is not a causative factor of CHD, and that high CHD mortality in the high total cholesterol groups reflects only their high proportion of FH [familial hypercholesterolemia] cases.” (Ann Nutr Metab 2015)

It’s difficult to ignore the evidence showing that high cholesterol is protective, and low cholesterol is harmful, and continue believing that the problem is cholesterol, simply because there is some association between high cholesterol and heart disease. It’s even more difficult once you see that lowering cholesterol doesn’t fix things, but often makes everything much worse.

In order to do so, you really have to ignore all of the biological evidence regarding the metabolic effects of ongoing stress and chronic inflammation. And you have to completely disregard the science which shows the stress promoting inflammatory dangers of the breakdown products of the PUFAs, when they interact with normal physiological processes. You really have to just ignore everything except the ‘science’ which pushes the official hypothesis.

Because if you don’t, you’ll quickly start to realize that biological science has known what cholesterol is for a very long time, and that it makes complete sense for cholesterol to rise under stress. It will also start to be obvious that if stress can interfere with cholesterol turnover, and if lowering stress and improving thyroid function can bring cholesterol levels back to a reasonably optimal level, that the problem was always the ongoing biochemical stress, inflammation and metabolic interference, not cholesterol.

When you consider the many stress protective, anti-inflammatory, pro-metabolic effects of sugar, for example, in light of the traditional ‘diet-heart hypothesis’, and in light of the positive role sugar plays in relation to liver function, cholesterol production, and cholesterol conversion, everything can start to fall into place.

Is your doctor aware of the role played by cholesterol in biology, and the many ways it defends against stress, and the onset or progression of disease?

Has your doctor read this study (Annals of Nutrition & Metabolism 2015;66(suppl 4):1–116) and other related studies questioning the validity of the cholesterol or lipid hypothesis?


Tohoku J Exp Med. 2013 Mar;229(3):203-11. Low serum LDL cholesterol levels are associated with elevated mortality from liver cancer in Japan: the Ibaraki Prefectural health study. Saito N, Sairenchi T, Irie F, Iso H, Iimura K, Watanabe H, Muto T, Ota H.

Curr Oncol. 2008 Apr;15(2):76-7. Do statins prevent or promote cancer? Goldstein MR, Mascitelli L, Pezzetta F.

Clin Exp Med. 2003 Feb;2(4):171-4. An increase in lipoprotein oxidation and endogenous lipid peroxides in serum of obese women. Mutlu-Türkoğlu U, Oztezcan S, Telci A, Orhan Y, Aykaç-Toker G, Sivas A, Uysal M.

Int J Med Sci. 2015 Jan 22;12(3):223-33. Association between Statin Use and Cancer: Data Mining of a Spontaneous Reporting Database and a Claims Database. Fujimoto M, Higuchi T, Hosomi K, Takada M.

Clin Biochem. 2010 Oct;43(15):1220-4. Malondialdehyde (MDA) and protein carbonyl (PCO) levels as biomarkers of oxidative stress in subjects with familial hypercholesterolemia. Pirinccioglu AG, Gökalp D, Pirinccioglu M, Kizil G, Kizil M.

J Epidemiol. 2011;21(1):67-74. Low Cholesterol is Associated With Mortality From Stroke, Heart Disease, and Cancer: The Jichi Medical School Cohort Study. Nago N, Ishikawa S, Goto T, Kayaba K.

Eur J Cancer Prev. 2018 Nov;27(6):570-576. Is low cholesterol a risk factor for cancer mortality? Parsa N, Taravatmanesh S, Trevisan M.

QJM: An International Journal of Medicine, Volume 105, Issue 4, April 2012, Pages 383–388, The statin-low cholesterol-cancer conundrum. U. Ravnskov, K.S. McCully, P.J. Rosch.

Cancer Epidemiol Biomarkers Prev. 2013 Sep;22(9):1529-37. Long-term statin use and risk of ductal and lobular breast cancer among women 55-74 years of age. McDougall JA, Malone KE, Daling JR, Cushing-Haugen KL, Porter PL, Li CI.

Aust N Z J Med. 1994 Feb;24(1):113-9. Review. Low cholesterol and risk of non-coronary mortality. Simes RJ.

Nature Communications volume 8, Article number: 14241 (2017). Dietary cholesterol promotes repair of demyelinated lesions in the adult brain. Stefan A. Berghoff, Nina Gerndt, Jan Winchenbach, Sina K. Stumpf, Leon Hosang, Francesca Odoardi, Torben Ruhwedel, Carolin Böhler, Benoit Barrette, Ruth Stassart, David Liebetanz, Payam Dibaj, Wiebke Möbius, Julia M. Edgar & Gesine Saher.

European Heart Journal, Volume 38, Issue 32, 21 August 2017, Pages 2478–2486. Extreme high high-density lipoprotein cholesterol is paradoxically associated with high mortality in men and women: two prospective cohort studies. Christian M. Madsen, Anette Varbo, Børge G. Nordestgaard.

The Journal of Clinical Endocrinology & Metabolism, Volume 103, Issue 1, January 2018, Pages 75–84, Statins Affect Skeletal Muscle Performance: Evidence for Disturbances in Energy Metabolism. Neeltje A E Allard, Tom J J Schirris, Rebecca J Verheggen, Frans G M Russel, Richard J Rodenburg, Jan A M Smeitink, Paul D Thompson, Maria T E Hopman, Silvie Timmers.

Open Journal of Endocrine and Metabolic DiseasesVol. 3 No. 3 (2013). The Ugly Side of Statins. Systemic Appraisal of the Contemporary Un-Known Unknowns. Sherif Sultan, Niamh Hynes.

Bull Exp Biol Med. 2010 Aug;149(2):184-6. English, Russian. Interrelation between malonyl dialdehyde-dependent modification and cholesterol content in low-density lipoproteins. Tikhaze AK, Viigimaa M, Konovalova GG, Kumskova EM, Abina EA, Zemtsovskaya G, Yanushevskaya EV, Vlasik TN, Lankin VZ.

N Engl J Med. 2017 Sep 21;377(12):1119-1131. Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease. Ridker PM, Everett BM, Thuren T, MacFadyen JG, Chang WH, Ballantyne C, Fonseca F, Nicolau J, Koenig W, Anker SD, Kastelein JJP, Cornel JH, Pais P, Pella D, Genest J, Cifkova R, Lorenzatti A, Forster T, Kobalava Z, Vida-Simiti L, Flather M, Shimokawa H, Ogawa H, Dellborg M, Rossi PRF, Troquay RPT, Libby P, Glynn RJ; CANTOS Trial Group.

Int J Cardiol. 2010 Oct 29;144(3):394-8. Low serum LDL cholesterol in patients with type 2 diabetes: an analysis on two different patient populations. Saely CH, Eber B, Pfeiffer KP, Drexel H; LIIFE-IN-LIFE study group.

Mol Nutr Food Res. 2005 Nov;49(11):1075-82. Review. The role of dietary oxidized cholesterol and oxidized fatty acids in the development of atherosclerosis. Staprans I, Pan XM, Rapp JH, Feingold KR.

J Atheroscler Thromb. 2012;19(11):986-98. Dietary cholesterol oxidation products accelerate plaque destabilization and rupture associated with monocyte infiltration/activation via the MCP-1-CCR2 pathway in mouse brachiocephalic arteries: therapeutic effects of ezetimibe. Sato K, Nakano K, Katsuki S, Matoba T, Osada K, Sawamura T, Sunagawa K, Egashira K.

Arterioscler Thromb Vasc Biol. 1998 Mar;18(3):415-22. LDL hypercholesterolemia is associated with accumulation of oxidized LDL, atherosclerotic plaque growth, and compensatory vessel enlargement in coronary arteries of miniature pigs. Holvoet P, Theilmeier G, Shivalkar B, Flameng W, Collen D.

Biomed Res Int. 2014;2014:598612. Effects of Dietary Cholesterol and Its Oxidation Products on Pathological Lesions and Cholesterol and Lipid Oxidation in the Rabbit Liver. Hur SJ, Nam KC, Min B, Du M, Seo KI, Ahn DU.

J Cardiovasc Pharmacol. 2007 Apr;49(4):246-52. Oxidation of low-density lipoprotein cholesterol following administration of poloxamer 407 to mice results from an indirect effect. Johnston TP, Zhou X.

Arterioscler Thromb Vasc Biol. 2002 Apr 1;22(4):662-6. Increased circulating malondialdehyde-modified LDL levels in patients with coronary artery diseases and their association with peak sizes of LDL particles. Tanaga K, Bujo H, Inoue M, Mikami K, Kotani K, Takahashi K, Kanno T, Saito Y.

Scientific Reports volume 7, Article number: 39982 (2017). Association between reductions in low-density lipoprotein cholesterol with statin therapy and the risk of new-onset diabetes: a meta-analysis. Shaohua Wang, Rongrong Cai, Yang Yuan, Zac Varghese, John Moorhead & Xiong Z. Ruan.

PLoS One. 2013;8(2):e55188. Localization of Oxidized Low-Density Lipoprotein and Its Relation to Plaque Morphology in Human Coronary Artery. Uchida Y, Maezawa Y, Uchida Y, Hiruta N, Shimoyama E, Kawai S.

Mol Nutr Food Res. 2005 Nov;49(11):1044-9. Review. 4-Hydroxynonenal and cholesterol oxidation products in atherosclerosis. Leonarduzzi G, Chiarpotto E, Biasi F, Poli G.

Biochem Med Metab Biol. 1987 Apr;37(2):213-9. The relationship of serum vitamin A, cholesterol, and triglycerides to the incidence of ovarian cancer. Das NP, Ma CW, Salmon YM.

Mol Aspects Med. 2009 Jun;30(3):180-9. Cholesterol oxidation products in the vascular remodeling due to atherosclerosis. Poli G, Sottero B, Gargiulo S, Leonarduzzi G.

Curr Med Chem. 2009;16(6):685-705. Review. Cholesterol oxidation products and disease: an emerging topic of interest in medicinal chemistry. Sottero B, Gamba P, Gargiulo S, Leonarduzzi G, Poli G.

Front Aging Neurosci. 2015 Jun 19;7:119. Oxidized cholesterol as the driving force behind the development of Alzheimer’s disease. Gamba P, Testa G, Gargiulo S, Staurenghi E, Poli G, Leonarduzzi G.

Blood Press. 2010 Jun;19(3):164-8. Malondialdehyde-modified low-density lipoproteins as biomarker for atherosclerosis. Viigimaa M, Abina J, Zemtsovskaya G, Tikhaze A, Konovalova G, Kumskova E, Lankin V.

Blood. 2003 Sep 1;102(5):1732-9. Heme and lipid peroxides in hemoglobin-modified low-density lipoprotein mediate cell survival and adaptation to oxidative stress. Asatryan L, Ziouzenkova O, Duncan R, Sevanian A.


J Am Geriatr Soc. 2003 Jul;51(7):991-6. Low total cholesterol and increased risk of dying: are low levels clinical warning signs in the elderly? Results from the Italian Longitudinal Study on Aging. Brescianini S1, Maggi S, Farchi G, Mariotti S, Di Carlo A, Baldereschi M, Inzitari D; ILSA Group.

Am J Physiol Cell Physiol. 2015 Oct 15;309(8):C522-31. The impact of statins on biological characteristics of stem cells provides a novel explanation for their pleiotropic beneficial and adverse clinical effects. Izadpanah R, Schächtele DJ, Pfnür AB, Lin D, Slakey DP, Kadowitz PJ, Alt EU.

Biochem Biophys Res Commun. 2014 Apr 11;446(3):709-13. Oxysterols and symptomatic versus asymptomatic human atherosclerotic plaque. Khatib S, Vaya J.

Atherosclerosis. 1996 Apr 5;121(2):267-73. High plasma insulin is associated with lower LDL cholesterol in elderly individuals. Strandberg TE, Tilvis RS, Lindberg O, Valvanne J, Sairanen S, Ehnholm C, Tuomilehto J.

Lipids in Health and Disease volume 16, Article number: 188 (2017). Current knowledge on the mechanism of atherosclerosis and pro-atherosclerotic properties of oxysterols. Adam Zmysłowski & Arkadiusz Szterk.

Circulation. 1998 Oct 13;98(15):1487-94. Oxidized LDL and malondialdehyde-modified LDL in patients with acute coronary syndromes and stable coronary artery disease. Holvoet P, Vanhaecke J, Janssens S, Van de Werf F, Collen D.

Am J Cardiovasc Dis. 2013;3(1):17-26. Interaction between sphingomyelin and oxysterols contributes to atherosclerosis and sudden death. Kummerow FA.

Expert Rev Clin Pharmacol. 2015 Mar;8(2):189-99. Statins stimulate atherosclerosis and heart failure: pharmacological mechanisms. Okuyama H, Langsjoen PH, Hamazaki T, Ogushi Y, Hama R, Kobayashi T, Uchino H.

Chronic Dis Transl Med. 2017 May 25;3(2):89-94. Association between circulating oxidized low-density lipoprotein and atherosclerotic cardiovascular disease. Gao S, Liu J.


Image: David Hammerstein
“¿Oscurantismo o acceso abierto a los datos sobre los medicamentos?”

You may also like...

Leave a Reply

Your email address will not be published. Required fields are marked *

Please "like" us:Already liked? You can close this