Hanging with the wrong crowd: how cholesterol got a bad name

Jun 16

Hidden truths are unspoken lies

There is an ongoing uproar in the realm of metabolic disease and nutrition research as it reassesses the role that saturated fats and dietary cholesterol play in cardiovascular disease, as well as other chronic ills. Recent findings are, in truth, not exactly new: researchers are rather unearthing and meta-analyzing old evidence which has been unquestionably eclipsed by greedy processed food corporations and, quite conceivably, pharmaceutical companies. Systematic reviews have thus brought to light dismissed and muzzled comprehensive evidence from studies dating as far back as the sixties, that clearly ended up disproving the low-fat/high carb hoax spearheaded and lobbied by companies with a vested interest in promoting artificial foods, particularly industrial seed oil companies. Allegations against saturated fats date back to the ‘60s, when the US sugar industry went as far as sponsoring a literature review by Harvard scientists that downplayed the risks of sugar and chastised fats. The Archer-Daniels-Midland Company, a processed food multinational, helmed a crusade against saturated fats and cholesterol, so it could freely flood the market with carcinogenic (and overabundant) soybean oil.

One systematic review from 2019 looked at 19 cohort studies involving over 68,000 participants and relayed that 16 of these studies had found an inverse relationship between LDL cholesterol and all-cause mortality. Much of the biased medical research on dietary fats conducted between the mid-sixties and early seventies was funded by a margarine company looking for ways to bolster its sales, by proving that saturated fats and dietary cholesterol were the culprit in cardiovascular disease; when research conclusions massively failed to fit its agenda, revealing instead a clear correlation between high mortality and polyunsaturated fats, or PUFAs (industrial seed oils, aka vegetable oils, and hydrogenated fats like margarine), findings were kept under wraps and researchers silenced. Processed food manufacturers are in the dock now for the use of sugars and killer fats, but it will be a long time before their lies and evil intents are effectively exposed, or enough voices are amplified so all Americans are taught to steer clear of junk and processed foods. Furthermore, the practice by food companies of funding research that magically corroborates their phony health claims is still ongoing and not so easy to undercut.

To upend the saturated fat tirade, scientists across the board have been leading with evidence that cholesterol, in and for itself, cannot be indicted for the rise in cardiovascular disease incidence and higher risk threshold. Rather, they have confirmed that a diet high in sugars and PUFAs is the real scourge of modern nutrition. So as to appreciate that the hypothesis of high LDL being a driver of heart attacks does not stack up with the science, the biology of cholesterol must first be understood.

The many functions of cholesterol: LDL and HDL

Cholesterol is a waxy, fatty substance, and it is an essential, versatile constituent of human biology with important immunological functions. It makes up 30% of our cell membranes, and modulates their fluidity; it is the backbone of steroid hormones like cortisol (our stress and immunity hormone) and sex hormones (testosterone, estrogen, progesterone, etc); it forms the basis of our Vitamin D; it is a precursor to bile acids, used in digestion to facilitate digestion and absorption of lipids and of fat-soluble vitamins A, D, E, and K; it regulates sodium and water balance; it insulates nerve and brain cells.

However, the term ‘cholesterol’ is loosely used, in an effort to facilitate physician-patient interactions as well as in lay medical and nutrition literature, as proxy for its carrier lipoproteins, LDL (low density lipoproteins) and HDL (high density lipoproteins), and their actual cholesterol load. Lipoproteins are molecules that have the ability to chemically combine with lipids. Given that fats are essential for life, they must travel around the body, but, since they cannot dissolve in a fluid, if they were released into the bloodstream as they are, they would erratically form clumps and obstruct blood vessels. In order to safely reach the target organs and tissues, fats recruit these transporter proteins, that envelop fat particles tight and shuttle them around. In simple terms, the LDL on blood tests is the lipoprotein that brings cholesterol from your liver to the heart and tissues, and HDL is the lipoprotein that fetches it from the heart and tissues back to the liver, which explains why the former has a bad reputation, while the latter is touted as a savior.

Hanging with the wrong crowd

Alas, things aren’t quite so cut and dry: all of this would happen without a hitch, if a little molecule known as glucose did not interfere. Let’s take a look, step by step, at the damaging effects that sugar has on cholesterol pathways, and consequently, on our cardiovascular health:

1.The liver manufactures 80% of the cholesterol the body needs, with the rest coming from exogenous sources. The liver then sends it out into circulation, nicely packaged in small particles collectively labeled as VLDL (very low-density lipoprotein), which contain both triglycerides and cholesterol; each VLDL particle is bound by a carrier protein called Apo B 100, capable of fraternizing with both lipids and fluids. [For future reference, it is worth noting that VLDL secretion is significantly increased in states of insulin resistance.] Most triglycerides (fats) are released into the bloodstream and donated to tissues for energy; the particles continue their journey, but having lost some of the lipid cargo, they are at this point labeled as LDL (low-density lipoprotein), which deliver cholesterol to cells, wherever in the body it is needed.

2. LDL particles can either travel around and be internalized by cells to carry out different functions, or they can be taken back up by the liver to be converted to bile acids and secreted into the intestines. The biochemical ‘key’ these LDL particles use to enter the liver is the very Apo B 100 protein located on their outer layer, and the gateway is a receptor located on the liver; if all goes well, the liver receptor recognizes the Apo B 100 protein, and lets the cholesterol particles in.

3.Trouble starts when liver and tissue receptors begin failing to recognize the Apo B 100 on the cholesterol molecule because it has been ‘disfigured’ by structural damage and oxidation caused by glycation – to put it in simple terms, the Apo B 100 protein particle is sugar-coated. This phenomenon happens when sugar metabolism is downregulated, due to insulin resistance: under normal conditions, the carbohydrates we ingest are broken down to glucose molecules to be used for energy by the cells, but if cells are insulin resistant, glucose molecules are locked out of tissue cells and go off to freely circulate in the blood, binding to lipoproteins (and other proteins), damaging them and causing them to shrink in size. Glycated/oxidized LDL particles cannot get into the liver, so they wander off.

4.The fate of these ‘frosted’ lipoproteins, which are commonly referred to as small dense LDL, is what causes concern. Once rejected by liver receptors, glycated/oxidized LDL particles start to accumulate in the bloodstream. This is the LDL particle count you would see on an accurate blood test, and it is a much better predictor of cardiovascular risk than the total amount of LDL, simply because these particles have all become smaller from oxidation (their amount in terms of volume is not indicative of how many are present, only their number is). The oxidized LDL particles floating in plasma now go out looking for accommodations, and they end up in - you may have guessed it, the arteries.

5.Scientists have resoundingly concluded that high levels of blood sugar damage the arteries, specifically the glycocalyx, a brush-like layer surrounding arteries that protects them and regulates their functions. More significantly, fluctuating levels of blood glucose exert damaging effects on the arteries, being associated with high levels of oxidation . Studies have in fact shown that damage to the arteries happens within a few hours of elevated blood glucose levels. Since an oxidized and inflamed glycocalyx lacks integrity, glycated LDL particles effortlessly carve micro-rifts to sneak into the lining of the arteries, along with circulating monocytes (a type of white blood cells present when inflammation or infections start). Once oxidized LDL particles and monocytes have nested in the arteries, the monocytes morph into macrophages (cells specialized in seeking out and removing dying or dead cells), able to detect the damaged Apo B 100, that ingest LDL particles in an effort to clean up waste material. These macrophages, fattened with LDL particles, form foam salts and aggregate into what is known as plaque; this can lead to narrowing of the arteries, decreased blood flow to the heart muscle (coronary artery disease), leg muscles (peripheral artery disease), or abrupt closure of an artery in the heart or brain; if the plaque gets brittle and ruptures under increased pressure, the broken molecules form clots that lead to a heart attack or stroke.

As it turns out, the road to metabolic disease is paved with sugar

The process of turning good LDL into bad LDL, hence, is not driven by saturated fats in the diet, it is driven by carbohydrates, a conclusion that is largely corroborated by statistics: two thirds of people who have heart attacks have diabetes or pre-diabetes. Comprehensive evidence from science points to insulin resistance, which leaves sugar floating around in the bloodstream, as the condition underpinning adverse cardiovascular outcomes, along with the bulk of modern ills. Moreover, excess blood sugar can contribute to the onset of atherosclerosis and cardiovascular events by means other than glycating and oxidizing LDL. Insulin resistance, caused by excess glucose in the blood, is the main driver of hypertension, or high blood pressure. Hypertension induces continuous stretching and bending of the arteries, causing microscopic tears in their delicate, one-cell-layer lining, making it even easier for glycated LDL particles and white blood cells to infiltrate. Additionally, excessive blood glucose causes systemic inflammation, which triggers blood hypercoagulability, making plaque prone to rupturing and clotting, hence leading to the formation of thromboses. Atherosclerosis is in fact scientifically defined as a systemic inflammatory process.

Functional testing

While there is no specific test as of yet for glycated LDL (gLDL), testing for glycated proteins in the body is therefore the best tool for predicting and preventing cardiovascular events. One test that is routinely carried out in clinical setting is the HbA1c test, also called glycated hemoglobin, glycosylated hemoglobin, A1c, or hemoglobin A1c test. A hemoglobin A1c (HbA1c) test measures the amount of blood sugar (glucose) attached to hemoglobin. Hemoglobin is the part of your red blood cells that carries oxygen from your lungs to the rest of your body. An HbA1c test shows what the average amount of glucose attached to hemoglobin has been over the past three months. It's a three-month average because that's typically how long a red blood cell lives. Although this test is used to check for diabetes and prediabetes, the detection of glycated hemoglobin is proxy for glycation of protein molecules in general: if hemoglobin is glycated, it can be be assumed lipoproteins are undergoing similar damage by the hands of circulating glucose. At home HbA1c test kits are available online.

Specific tests are available that can can be carried out to assess the presence of proatherogenic, small dense LDL through proxy markers. While a standard lipid panel will only give you the total amount of LDL present in the body, it provides no insight as to the number of particles circulating in the blood or the small dense LDL (glycated/oxidized) to large buoyant LDL (benign) ratio. A test called NMR LipoProfile® provides this information using nuclear magnetic resonance (NMR) spectroscopy to directly measure particle count and size. One of the best features of this test is that it assesses insulin resistance: the LP-IR Score, within this panel, is an insulin resistance marker where the higher your number, the greater probability of insulin resistance. For reference, you should have less than 1000 total LDL particles and less than 500 small LDL particles (the dense dangerous type).

Also, a test that measures an enzyme called Myeloperoxidase (MPO) can be carried out to detect the presence of the above mentioned white blood cells activated by oxidized LDL (perceived as an invader), inducing inflammation and making plaque prone to rupturing. MPO, a key enzyme in innate immunity and defense against pathogens, is a bad actor in the pathogenesis of atherosclerosis, since it oxidizes LDL, increases coronary calcium, can cause high blood pressure and lead to plaque rupture. To make matters worse, high levels of MPO also damage the protective HDL and makes it dysfunctional.

Do statins work?

Anyone reading this is at this point wondering whether statin medications are truly effective in lowering the risk of heart disease. The answer is provided by studies showing that cholesterol-lowering drugs do not increase life expectancy by more than a few days, and the reason is that statins act on liver receptors to increase uptake of undamaged LDL particles, but are unable to increase receptor sensitivity to glycated/oxidized LDL, which means that while in the long run they may lower the load of LDL that can be ‘sugar-coated’, they do nothing in terms of reversing glucose damage, although they do have the merit of exerting an anti-inflammatory effect, which could explain some of their functionality. The downside of statins is they may increase plasma glucose concentration, hence the chances of developing diabetes in susceptible individuals. Bottom line, if you are taking statins, and still eating more than your share of carbohydrates and unhealthy fats, chances are you are putting your eggs in the wrong basket.

The low carb solution

As a general caveat, for those seeking to lower their carb intake, please do so with the help of a professional: while it can be quite correctly argued that a low-carb diet is beneficial to all adults, with respect to sugar metabolism there is such a thing as dose relativity. We are now aware that metabolic illnesses stem from insulin resistance, but, while individuals with metabolic disruptions might require a maximum intake of 20 to 30 grams per day to reverse their conditions and avert cardiovascular disease, others are enabled by their genetics, epigenetics and environmental factors to maintain healthy insulin sensitivity at quite a high level of carbohydrate intake. Differences in thresholds warrant varying degrees of carbohydrate consumption and recalibrating is feasible as insulin sensitivity is restored. Lab test results can provide medical insight into metabolic efficiency and eventual worsening or improvements. Genetics, body shape, ethnicity, sex and age must all be accounted for when making decisions pertaining to a feeding regimen, particularly if cardiovascular disease risk is of concern.

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References:

https://pubmed.ncbi.nlm.nih.gov/19364995/

https://pubmed.ncbi.nlm.nih.gov/27292972/

https://www.oatext.com/development-of-the-damaged-glycocalyx-hypothesis-a-review.php

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2824152/

https://pubmed.ncbi.nlm.nih.gov/21735388/

https://pubmed.ncbi.nlm.nih.gov/26268692/

https://www.bmj.com/content/353/bmj.i1246

https://pubmed.ncbi.nlm.nih.gov/28526025/

https://www.cell.com/trends/endocrinology-metabolism/comments/S1043-2760(11)00072-5#:~:text=Insulin%20resistance%20(IR)%20affects%20not,despite%20the%20increased%20VLDL%20secretion.

https://www.ahajournals.org/doi/10.1161/ATVBAHA.114.303565#:~:text=During%20the%20development%20and%20exacerbation,physical%20bulk%20of%20developing%20plaques.