Cholesterol

TL:DR: Measuring LDL is not sufficient to assess cardiovascular risk. One must measure the number of apoB and Lp(a) particles – which are the particles that get inflamed in the endothelium that causes atherosclerosis.  Eating cholesterol has very little impact on cholesterol levels in body. Dietary cholesterol is not absorbed and excreted in gut. 

 

What is cholesterol?

Cholesterol is a waxy lipid (non-water soluble molecule) that is made in the body. 20% of cholesterol is synthesized in the liver and 80% in other cells. It can be found in every cell in the body. Cholesterol is essential to life (to protect our nerves, make cell tissues / hormones): we eat, make, store and excrete it.

Cholesterol exists in 2 forms:

• unesterified or “free cholesterol” (UC)
• esterified (CE)

The form of cholesterol determines how we absorb or store it.

 

Where does cholesterol come from?

• Exogenous cholesterol – this refers to cholesterol that we eat.
• Endogenous cholesterol – this refers to cholesterol that we make in our liver and other cells. Most of the time this is sufficient for our body’s needs.

 

How does cholesterol move around?

Cholesterol is hydrophobic, which means it cannot move in water. It is carried around the water in liproproteins.

Liproproteins are produced in the liver and the intestines. Lipoproteins transport cholesterol and triglycerides to cells and muscle tissues that need them for energy (which gets oxidized into ATP).

 

Why do people think that LDL cholesterol is “bad”?

High LDL cholesterol is often seen as a risk factor for cardiovascular disease and atherosclerosis.

This is because LDL particles transport apoB particles that can get inflamed in the artery wall.

Atherosclerosis or inflammation in the arteries occurs when a sterol becomes engulfed in a macrophage in an artery wall. The only way sterols are carried in is when they are carried in by an apoB lipoprotein. The apoB containing particle penetrates the endothelium, and gets retained in the subendothelial space, and an inflammatory response occurs, immune cells arrive, and “fixes” the apoB particle in the place. When the artery wall is covered with plaque and narrows, it reduces blood flow to the heart and can cause a heart attack.

Insults to the endothelium increases the permeability and the capacity for macrophages to take residence in the “space” in the subendothelium.  When inflammation occurs, it creates more space for more apoB carrying particles to get in and get “stuck”. Things that damage the endothelium lining your blood vessels include:

• Uric acid
• Hyperinsulinemia
• Elevated glucose levels
• Homocysteine

95% of the apoB are in LDL-P (but can also be found in VLDL, IDL).

 

 

LDL

LDL-C vs LDL-P

When you measure LDL in a standard blood test, what you’re measuring is LDL-C. LDL-C refers to the amount of cholesterol in the low density lipoprotein. This is used as a way to assess risk of atherosclerosis but is not the best measure.

A better way to quantify risk of atherosclerosis is to measure LDL-P (or apoB) as this is the best predictor of adverse cardiac events. LDL-P refers to the number of LDL particles in a certain volume. You can also use apoB number to measure LDL-P because each LDL-P particle only has one apoB.

The higher the LDL-P, the higher the risk. If you want to stop atherosclerosis, you must lower the LDL-P (apoB) number.

LDL-C is only a good predictor of cardiovascular risk if LDL-C is concordant with LDL-P.

There is no way to tell if LDL-P and LDL-C are concordant or discordant in patients without measuring both.

Discordance between LDL-C and LDL-P is even greater in populations with metabolic syndrome, including patients with diabetes (due to over-crowding of particles “boats” vs cholesterol “cargo”).

Measuring C is also not reflective of the flux in the system – how much cholesterol there are in the cells and how much forward or reverse cholesterol transportation (i.e. movement) there is.

 

HDL

HDL-P particles carry cholesterol from the subendothelial space back to the liver. (LDL particles carry cholesterol to the muscles and cells.)

HDL particles have multiple antioxidative functions by metabolizing oxidized LDL particles and preventing their accumulation.

HDL-P carry the apoA apoprotein. LDL-P carry the apoB apoprotein.

More HDL particles are good. Smaller HDL-P particles appear to be more protective than larger ones.

A higher HDL-C does not imply more HDL particles. Higher HDL-C levels are often driven by a disproportionate rise in HDL size, not HDL-P.

Therefore artificially increasing HDL-C with drugs isn’t going to fix the problem.

Exercise increases HDL-C and HDL-P. Moderate intensity aerobic exercise seems to be sufficient to increase HDL, however this appears to be frequency/duration dependant (at least 300 min a week, moderately intensity). It also appears to be gender sensitive (men see more HDL benefits from exercise than women).

Low HDL-cholesterol and high triglyceride is four times more predictive of myocardial infarction (MI is the clinical term for heart attack), than high LDL-cholesterol.

 

apoA

apolipoprotein A is found on the HDL particle and each HDL particle can have multiple apoA on it. apoA-1 particles use a suction system to suck sterol [cholesterol] out of the macrophages. That’s why apoA/HDL is thought of as good.

 

apoB

Every LDL has 1 apoB-100 particle on it.

So apoB is basically just another way of saying LDL particle count. The main structural protein that enwraps lipids in our plasma is apolipoprotein B. apoB is made in the liver and small intestine. The causal relationship between apoB and atherosclerosis is very strong. Lowering apoB by 50% is good.

apoB is a marker of all atherogenic particles including, if present, Lp(a).

The more apoB particles you have, the more problems you have. Most people with low HDL cholesterol also have high apoB, which is what’s driving atherosclerosis.

• Optimal: <80 mg/dl
• Borderline: 80-120 mg/dl (mine is 0.91 g/L)
• Increased risk: >120 mg/dl

Statins lower apoB particles.

Can take drugs (e.g. PCSK9 inhibitors) or to the lower the amount of lipoprotein, you can to lower the amount of cargo they have to carry. i.e.means lowering triglycerides and lowering cholesterol. To lower cholesterol, you need to reduce the synthesis of cholesterol, or reduce the reabsorption of cholesterol. NOTE: It does NOT include reducing the intake of dietary cholesterol since that features very little into how much cholesterol you have since most of that is not absorbed.

High apoB is a necessary but not sufficient driver of atherosclerosis.

Nutritionally, apoB is the concentration of LDL particles that carries cholesterol and trigycerides. Anything that lowers cholesterol or triglycerides, lowers apoB. Triglycerides are generally driven by carbohydrate intake. So if you reduce carb intake (while keeping saturated fat low), you will reduce apoB.

 

Lp(a)

Lipoprotein(a) is an LDL-like particle with additional apolipoproteins bound to it – apo(a) and apoB.

apo(a) binds to apoB on some LDL particles, converting the LDL particle to Lp(a) particle.

Elevated Lp(a) is associated with increased risk of atherosclerosis, aortic stenosis, and venous thrombosis. If one has high Lp(a) and a bad family history or positive CAC, etc., he should lower all other risk factors (apoB and metabolic parameters like BP, uric acid, homocysteine, etc.) to the extent possible.

Why? Lp(a) carries a higher number of oxidized phospholipids which sends signals that will drive pro-inflammatory, maybe pro-thrombotic, and pro-calcifying signals to endothelial, muscular and aortic valve cells.

• If your Lp(a) is elevated, your LDL will be elevated.
• When Lp(a) is high, but apoB is normal, Lp(a) may not add that much risk
• When Lp(a) and apoB are both high, it’s a double whammy

About 20% of people have an elevated Lp(a), which is the greatest genetic driver of atherosclerosis. This is genetic so lifestyle interventions cannot lower your Lp(a).

Testing for Lp(a)

An Lp(a) test is one of the five most important blood tests you should ever do, and you only need to do it once. Lp(a) levels is stable over your lifetime – can be tested from the age of 18.

• Optimal: <30 mg/dl
• Borderline: 30-50 mg/dl (mine is 32.3 mg/dl)
• Increased risk: >50 mg/dl

Most labs measure in mg/dl (which measures the mass).  It would be better if it is measured in nmol/L – better indication of number of particles.

What do to

Even though there’s no specific therapy for high Lp(a), it doesn’t mean you can’t do anything.

If you’re elevated (≥50 mg/dL), the best thing you can do at the moment is keep apoB as low as possible and manage all other risk factors that traffic with atherosclerotic cardiovascular disease (hypertension, smoking, insulin resistance, etc.)

• Eradicate apoB (Attia targets 30 mg/dl)
• Statins
• Use PCSK9 inhibitors

Anybody that has an elevated Lp(a) should immediately be screened for aortic stenosis, which is about a 2-4x increase in said patients. Get a baseline look at your aortic valve using an echocardiogram. If you can’t get a good enough view, get a cardiac MRI. It is important to identify aortic stenosis in its earliest stages because the earlier you intervene, the better the outcome.

 

Triglycerides

High triglycerides (TG) in the blood is a risk factor for cardiovascular disease. When there is too much triglycerides in the body so the body has to produce more lipoproteins to carry the cholesterol/triglycerides.

The higher the level of serum triglycerides, the greater the likelihood of discordance between LDL-C and LDL-P (and apoB).

The higher the level of metabolic syndrome, the greater the discordance between LDL-C and LDL-P.

 

How do we measure cholesterol levels?

Most doctors use a standard lipid test to measure LDL-C (cholesterol content in low density lipoprotein), HDL-C (cholesterol content in high density lipoprotein) and triglycerides (TG).

Total cholesterol (TC) refers to all the cholesterol molecules (in every single lipoprotein) in a deciliter of your plasma. This metric is assayed (i.e. directly measured). You can also directly measure HDL-C. LDL-C is then calculated based on a formula:

LDL-C = TC – HDL-C – TG/5

(TG/5 is an estimation of VLDL because a VLDL particle has five times the amount of triglycerides and 1/5th the amount of cholesterol).

 

How to test for Lp(a), apoA and apoB in Singapore

You can walk in to Pathlabs and do a blood test without a doctor. Quest Diagnostics/Innoquest can also do it, but require a GP to order the tests.

Many GPs will not have heard of these tests but if you would prefer to do this via a GP so that the GP can interpret the results for you, you can go to Tucker Medical and see Dr Sak.

 

Insulin Resistance and LDL

Insulin resistant patients are at higher risk of getting atherosclerotic disease, because they tend to have very high LDL-P and apoB. High triglyceride / HDL cholesterol ratios tend to correspond to high apoB numbers.

 

Cholesterol in the Brain

Serum (blood) cholesterol has nothing to do with cholesterol in the brain. The brain makes all the cholesterol that it needs. There are no LDL particles delivering cholesterol to your brain. LDL particles do not fit through the blood brain barrier (apoB is too big). apoE is the protein transporter in the brain and this is what moves cholesterol around the brain.

 

Does eating cholesterol raise your cholesterol levels?

Eating dietary cholesterol has a very little impact on our blood or serum cholesterol levels.

Much of the cholesterol we eat is in the form of esterified cholesterol (CE). It is not absorbed and is excreted by our gut, leaving the body as stool.  For the body to absorb CE, it first has to de-esterify the cholesterol.

Eating more cholesterol (exogenous) is associated with decreased endogenous de novo cholesterol (cholesterol that you make), due to cholesterol homeostasis.

Extensive research has not shown evidence to support a role of dietary cholesterol in the development of cardiovascular disease. In fact, the recommendations of eating less than 300 mg of dietary cholesterol a day has been removed in the 2015–2020 Dietary Guidelines for Americans.

 

Does eating saturated fat raise your cholesterol levels?

For most people, increasing consumption of saturated fat will increase LDL.

 

How to lower cholesterol and cardiovascular risk?

• Eat less carbs / sugar. Sugar or (sucrose, high fructose corn syrup) increases plasma levels of triglycerides, VLDL and apoB, and reduces plasma levels of HDL-C and apoA-I.
• Eat less fructose. Fructose alone, has a similar but less harmful impact as that of fructose and glucose combined (i.e., sugar).
• Foods such as shrimp and eggs contain a high amount of cholesterol are ok. Neither of them have negative effects on serum cholesterol levels and are actually beneficial in improving cholesterol levels.
• Foods high in saturated fatty acids may increase the risk of CVD due to the saturated fatty acid content. However, epidemiology is confounded by people who consume more saturated fat typically also consuming unhealthy ingredients like refined carbohydrates. Consumption of a moderate amount of saturated fat is in our evolutionary history.
• Some argue that fat is ok, in the absence of sugar and starch.  Fat, in the absence of sugar and starch, does not raise serum triglycerides or other biomarkers of cardiovascular disease.
• Replacing saturated fat (meat, eggs, dairy, cheese) with monounsaturated fat (olive oil, avocado, nuts) is reported to lower LDL-P.
• Red Yeast Rice can reduce LDL (Thorne Research Choleast 900 – buy from iHerb)
• Improve metabolic health
• Exercise increases HDL and lowers triglycerides but this is frequency and dose dependant (need 300 minutes a week at moderate intensity). Women need even more exercise than men to reap this benefit.
• Stop smoking
• Reduce hypertension

 

Sources

YouTube: Dr Peter Attia: Redressing Dietary Guidelines
YouTube: Dr Peter Attia – An Advantaged Metabolic State: Human Performance, Resilience & Health
YouTube: Dr Peter Attia – The Straight Dope on Cholesterol Slides can be found here.
#210 – Lp(a) and its impact on heart disease | Benoît Arsenault, Ph.D.
YouTube: Dr Paul Mason – Ketogenic Diets and Cholesterol
Peter Attia ‘s Website on Cholesterol

 

The information here is for informational purposes only. This website does not provide medical, professional, or licensed advice and is not a substitute for consultation with a health care professional. The use of any information on this website is solely at your own risk.