Nutrition — Cholesterol

Posted on    by

This post relies heavily on the blog posts and podcasts of Peter Attia, specifically his nine part series of blog posts entitled “The Straight Dope on Cholesterol” as well as the podcasts episodes of the The Drive with Peter Attia with Tom Dayspring, Ron Kraus and the Deep Dive on Lp(a) podcast. Any mistakes in this post are mine. Please refer to the excellent source materials for more details.

Summary

  • Key Takeaways.
  • Cholesterol Function.
  • Cholesterol Sources.
  • Cholesterol = Bad: Traditional (Mistaken) Paradigm.
  • Cholesterol Transport: Traditional (Incomplete) View.
  • Cholesterol Measurement: LDL Amount (LDL-C)
  • Better Cholesterol Measurement LDL Particles (LDL-P).
  • Cholesterol Problems.
  • Role of HDL.
  • Cholesterol and Age.
  • LDL Lowering Pathways.
  • LDL Clearance.
  • Dietary Implications.
  • Lp(a).
  • Lp(a): Details.
  • Lp(a): Fixing Pathways.
  • Cholesterol Lowering Drugs.

Key takeaways.

  • Three main drivers the risk of heart disease:
    • High level of cholesterol (high number of cholesterol particles) = higher chance particles penetrate endothelial layer of artery wall and get stuck.
    • Damaged endothelial function = higher chance that particles penetrate and get stuck.
    • Inflammation = higher chance that plaque builds up, leading to high risk of CVD.
  • Risk of heart disease is a numbers game.
    • More “bad particles” = more risk.
  • Important to know the number of cholesterol particles in your bloodstream.
    • Standard panels measure cholesterol mass and don’t give you a particle count.
    • Cholesterol mass is not always aligned with particle count.
  • Some particles are worse than others – worry about:
    • LDL particles.
    • Lp(a) particles – specific type of LDL particle that is particularly harmful.
    • [HDL particles on average can be ignored.]
  • Measure relevant bio-markers:
    • Lipoprotein particles (number):
      • Lp(a), LDL-P.
    • Endothelial dysfunction:
      • Insulin, homocysteine, ADMA, and SDMA.
    • Inflammation:
      • Nonspecific: fibrinogen, hs-CRP.
      • Specific: oxLDL, Lp-PLA2, oxPL.
  • If you are at risk, there are three main pathways to fix high cholesterol:
    • Decrease synthesis in the liver.
    • Decrease absorption in the gut.
    • Increase removal by the liver.
  • Additional tests to understand which pathway is not working:
    • Synthesis test: plant sterol test.
    • Absorption test: desmosterol test.
    • If those are okay, the cholesterol issue is likely related to removal at the liver.
      • Usually, the problem is removal at the liver.
  • Drugs may help to fix cholesterol issues:
    • Statins:
      • Go-to drug for fixing LDL.
      • Reduces synthesis and (mainly) increases removal.
      • Don’t work to fix Lp(a).
      • May have long-term brain-impact.
      • Usage in combination with other drugs, supplements, diet.
    • PCSK9 inhibitors:
      • Increase cholesterol removal.
      • Can help reduce Lp(a).
      • So far no known side effects.
    • Promising drugs in development / trial phase include ASO.
    • Other drugs to consider include Niacin, but seemingly less favored.
  • Dietary fixes are tricky.
    • Low-carb diet.
      • Lowers triglycerides (TG).
      • Lowering TG may help to lower LDL particle production.
        • Less of a need for TG to be shuttled out of the liver.
    • Substitution of TG with fat may not work .
      • Saturated fat may lead to lower LDL removal for some.
      • Poly-unsaturated fats (especially omega-6) may increase oxidative stress for some.
      • Mono-unsaturated may work better as a substitute for carbs.
  • Supplements to consider:
    • Berberine:
      • Works on the same pathways as PCSK9 inhibitors.
      • Increases cholesterol removal.
    • Omega-3:
      • Lowers TG (which then helps lower LDL).
      • Works for some.

Introduction

  • Cholesterol is one of the three major classes of lipids in the body:
    • Cholesterol
    • Triglycerides (TG).
    • Phospholipids.
  • In the same class as fat (TG), but important differences in structure and function.
    • It contains carbon rings rather than long chains of carbon atoms.
    • Different activity in body.
  • Essential for life and generally good.
    • Structural component of cell membranes and building block for steroid hormones.
  • Each cell in the body can synthesize cholesterol, so it is not needed in the diet.
    • Occurs only in foods of animal origin.
  • Transported in the blood plasma inside protein particles (lipoproteins).
    • Insoluble in water.
  • Exists in two forms.
    • Free or unesterified (UC) and esterified (CE).
    • The form determines if we can absorb it or not, if we can store it or not.
  • Bad outcome:
    • Cholesterol ends up inside of the wall of an artery.
    • AND then leads to an inflammatory cascade which results in the obstruction of that artery.

Cholesterol Function.

  • Required by all cell membranes, produces steroid hormones and bile acids.
    • Every cell in our body is surrounded by a membrane.
    • Membranes regulate fluidity / permeability.
      • How the cell moves, interacts with other cells, and how it transports things in and out.
    • Cholesterol is one of the main building blocks used to make cell membranes.
    • Also serves an important role in the synthesis of vitamins (D) and steroid hormones, including sex hormones and bile acids.

 Cholesterol Source.

  • External:
    • 25% of the body’s cholesterol comes from the foods we eat.
      • Most of the cholesterol in our food (> 50%) is CE.
      • Only UC can be absorbed by the cells in our gut.
      • So most of the cholesterol we eat is not absorbed and excreted by the gut.
  • Internal:
    • Our body synthesizes most of our cholesterol (75%).
      • 20% of that is synthesized by the liver.
      • 80% is synthesized by the cells in our bodies themselves.
    • Re-absorption of the cholesterol we synthesize in our body is the dominant source of the cholesterol in our body.
      • Most of the cholesterol in our body was made by our body.
  • Eating cholesterol has very little impact on the cholesterol levels in your body.

Cholesterol = Bad: Traditional (Mistaken) Paradigm

  • Historical studies proposed that very high levels of saturated fat led to an increase in cholesterol.
  • Leading to the idea that a high cholesterol diet is bad.
  • Studies since pointed out several flaws with this hypothesis:
    • While a high level of cholesterol is associated with an increased risk of heart disease, many who suffer from heart disease have normal blood cholesterol level.
    • Cholesterol is directly synthesized in the body and excess dietary cholesterol is mainly excreted.
    • Even a diet very high in cholesterol has little, if any, impact on cholesterol levels.
    • Having said that, saturated fat may increase cholesterol in some cases by impeding the clearance of cholesterol by the liver (see below).

Lipoproteins

  • Cholesterol travels through the body.
    • Towards to the periphery and back to the liver.
  • Needs a carrier.
    • Insoluble.
    • Carried inside “something” around our bloodstream.
  • Lipoproteins:
    • The protein wrapped “vehicle”/”boat”.
    • Carries cholesterol, TG and phospholipids from the gut and liver to the periphery (muscles and fat cells).
    • Made up of thousands of molecules which encase the lipids.
    • Main function of is to deliver TG and phospholipids, not cholesterol:
      • Body cells don’t really need cholesterol, since they can make their own.
      • On lipoproteins, perhaps cholesterol is only there to provide structure.
      • Most of the cholesterol shuttled around traffics back to the liver, intestine, gets re-circulated or excreted.
  • Lipoprotein classification:
    • Lipoproteins contain both lipids and proteins.
      • Lipids = low density (cholesterol and TG).
      • Proteins = high density.
    • Ratio of lipid-to-proteins determines density.
  • Classification from lowest density to highest density:
    • Chylomicron.
      • Lowest density.
        • Very high on TG.
      • Originates in the gut.
      • Separate pathway from all other lipoproteins.
      • Does not convert into VLDL.
    • VLDL
      • Very Low Density Lipoprotein.
      • Made in the liver.
      • High on TG.
      • Particles shrink as they shed TG.
      • Mostly gets cleared or turned into IDL (few).
    • IDL
      • Intermediate Density Lipoprotein.
      • Made in the liver.
      • Also shrink as they shed TG.
      • Again, mostly cleared or turned into LDL (few).
    • LDL
      • Low Density Lipoprotein.
      • Made in the liver.
      • Lp(a) – special kind of LDL [See below].
    • HDL
      • High density lipoprotein.
      • Low on TG, small particle.
    • Inverse relationship between size and density:
      • VLDL particles are large.
      • HDL particles are small.

Apoproteins

  • Special proteins that reside on the (surface of) lipoproteins vehicles.
  • Essentially a marker to identify where a lipoprotein is going.

Apolipoproteins

  • Apoproteins that are bound to lipids:
    • apoA-I:
      • Good.
      • Mostly found in HDL.
    • apoB / apoB-100:
      • Bad
      • Mostly found in LDL.
    • apoC
      • apoC-III – inhibits cholesterol clearance by slowing lipoproteins binding to liver receptors.
    • apoD
    • apoE
      • Protein transporter in the brain.
      • In the body, binds most effectively to liver receptors.
  • More detail below.

Cholesterol Transport: Traditional (Incomplete) View

  • Cholesterol leaves the liver as VLDL and leaves the intestine as chylomicron.
  • VLDLs undergo a process of maturation:
    • Shed much their TG and phosphor “cargo” in the form of free fatty acid where it is needed.
    • Doing so makes them smaller and denser.
    • Most get cleared, some don’t (remnants).
    • Some remnant VLDL turns into IDL, then into LDL
    • Much of the circulating LDL was created de novo from the liver.
  • Chylomicrons shed their cargo and just become smaller.
    • They don’t change into any other particle.
  • HDL is responsible for taking excess cholesterol from the tissues within the body.
    • Including removing cholesterol from the arteries.
    • Traffics cholesterol to the liver – “direct reverse cholesterol transport”. [good]
    • Traffics cholesterol to the intestine – TICE. (see below)
    • Transfers cholesterol to other lipoproteins (VLDL, IDL, LDL) – CETP. (see below)
  • Other lipoproteins (VLDL, IDL, LDL) deliver cholesterol back to the liver or the intestine, or stay in circulation.
    • To the liver: “indirect reverse cholesterol transport.” [good]
    • To the intestine – TICE.
    • Stay in circulation.
      • May penetrate and deliver its cholesterol load to the artery walls. [bad]

Cholesterol Measurement: LDL Amount (LDL-C).

  • Levels are measured in:
    • Milligrams (mg) of cholesterol per deciliter (dL) of blood (US).
    • Millimoles (mmol) per liter (L) of blood (Europe).
  • Standard blood tests or lipid panels typically measure or estimate LDL-C.
    • The amount of cholesterol carried by LDL.
    • Measure total cholesterol (TC).
      • Includes all types of cholesterol.
      • Chylomicrons don’t stay around very long, so assume they are zero.
      • TC = HDL + VLDL + LDL (simplified).
    • Isolate LDL:
      • HDL is easily separated and measured.
      • VLDL can be estimated:
        • In a fasting state, if you measure TG (separately), some of that TG is inside the VLDL particles.
        • Estimate cholesterol in VLDL as one-fifth of the measured TG (based on generic ratio of TG/cholesterol in VLDL).
      • LDL (estimate) = TC minus HDL minus one-fifth of TG.

Better Cholesterol Measurement LDL Particles (LDL-P).

  • Numbers game:
    • The higher LDP-P, the number of particles circulating in the bloodstream, the higher the chance that particles may penetrate the artery layers.
  • The LDL-C and LDL-P marker values don’t always match-up:
    • Some people have low LDL-C and high LDP-P (discordant values).
    • Discordant values may lead to underestimating risks.
    • LDL-C is only a good predictor of adverse cardiac events when it is concordant with LDL-P; otherwise it is a poor predictor of risk.
    • 50% of people with heart disease have normal “traditional” lipid values (ie, LDL-C).
  • If you are “allowed” to know only one metric to understand your risk of heart disease it would be the number of apoB particles (90-95% of which are LDLs) in your plasma.
  • If this number is high, you are at risk of atherosclerosis.

Cholesterol Problems

  • Atherosclerosis:
    • The accumulation of sterols and inflammatory cells within an artery wall which may (or may not) narrow the lumen of the artery.
    • Leading cause of death, even ahead of all forms of cancer combined.
    • Most commonly within coronary arteries, but also carotid or cerebral arteries
  • Atherosclerosis eventually results in sudden plaque ruptures, cardiovascular disease, stroke and other vascular diseases.
  • Process:
    • apoB-containing lipoprotein particle violates a layer [the endothelial layer] inside the artery’s wall and stays there.
    • Accumulated apoB particles (mostly LDL, but also Lp(a)), oxidize and trigger an inflammatory response.
    • Immune cells (various types of white blood cells) arrive.
    • The immune response is initially beneficial but can become mal-adaptive:
      • Immune cells may create more room for LDL particles between artery layers.
    • Ultimately results in the formation of a plaque.
  • The most common apoB containing lipoprotein in this process is the LDL particle.
    • However, Lp(a) and other apoB containing lipoproteins play a role also, especially in the insulin resistant person.
    • An insulin resistant person has high levels of TG. TG is carried around in VLDL. Likely leads to elevated VLDL particle numbers. VLDL may also penetrate the artery walls.
  • HDL particles can easily go in and out of the arterial wall and do so to clean up cholesterol.
  • If you want to stop atherosclerosis, you must lower the LDL particle number.
  • Particle size may not be as important:
    • The key thing that matters is the number of LDL particles, small, large or mixed.
  • Ultimately, the risk of CVD is driven by three things (bio-markers in parentheses)
    • Lipoproteins (Lp[a], LDL-P, small LDL-P, VLDL remnant)
    • Inflammation (nonspecific: fibrinogen, hs-CRP; specific: oxLDL, Lp-PLA2, oxPL)
    • Endothelial dysfunction (insulin, Hcy, ADMA, and SDMA)

Role of HDL.

  • The smallest of the lipoprotein particles.
    • Highest proportion of protein (dense) to TG/cholesterol (not dense).
  • Transport cholesterol out of artery walls, reduce particle accumulation, and thus help prevent or even regress atherosclerosis.
  • Also carry many other lipid and protein species that help clear inflammation (by absorbing cholesterol) and prevent clotting.
  • Because of this, sometimes referred to as “good cholesterol”.
  • But cholesterol transport system is very complicated.
  • While HDL is import and and needed, it no longer makes sense to assume that all HDL does is good things.
    • Sometimes “good” HDL shed their cholesterol to “bad” apoB particles (CETP – see below).
    • So does good cholesterol suddenly change into bad cholesterol?
  • So raising HDL-C (with drugs) has not provided benefits in the reduction of cardiovascular events.

Cholesterol and Age.

  • Age is the strongest predictor of risk.
  • The longer your artery walls are exposed to the impact of apoB particles, the more likely they are to be damaged.
  • So you can only delay adverse impact.

LDL Lowering Pathways.

  • Main options:
    • Lower the amount of cholesterol you synthesize.
      • Lower the amount of TG you carry around.
    • Lower the amount of cholesterol that you reabsorb.
    • Increase clearance of LDL particles (driven by the LDL receptors).
    • Inhibit production of other elements (such as apolipoproteins).
  • Lowering LDL synthesis is usually not the best option (typically not the major issue).
  • If you do attack LDL synthesis:
    • Drugs:
      • Statins work (partially) by addressing LDL synthesis.
      • See drugs descriptions below.
    • Diet or supplements:
      • Reduce production of LDL by lowering the cargo level (TG).
        • Omega-3:
          • May lower production of TG.
        • Lower carb / sugar intake:
          • May lower production of TG.
          • Sugar increases levels of TG , VLDL and apoB (bad).
          • Sugar reduces plasma levels of HDL-C and apoA-I (bad).
      • Increase fat intake.
        • In the absence of sugar and starch, does not raise TG.
        • In some (PPAR alpha and gamma gene variants) saturated fat may increase TG.
        • Issue can be addressed by substituting saturated fats with PUFAs.
        • Some studies that PUFAs can be harmful and help produce free radicals and increase inflammation
        • Safest option may be MUFA.
      • Note that trying to lower synthesis through diet may lead to lower removal of cholesterol.
        • Certain fats may negatively impact removal of LDL.
          • Saturated fat can impede the function of LDL receptors, causing greater levels of LDL in the blood.
          • Seems to still be an undecided matter.
  • Cholesterol absorption typically not the issue either.
    • Depends on genetic ability to absorb cholesterol.
    • ABC8 gene.
  • Problems with LDL are often the result of a lower number of LDL receptors.
    • Important to understand if you have any genetic issue linked to LDL receptors.
      • Those with genetic predisposition to have lower LDL receptor activity should probably eat less, or in some cases, very low fat diets (see above).
      • Key genes are LDLR and PCSK9.

Dietary Implications.

  • Avoid trans-fats.
    • Rare in nature.
    • Often created when poly-unsaturated fats are treated to increase shelf life.
    • Avoid pre-prepared meals and foods, deep fried foods.
  • Prefer mono-unsaturated fats over poly-unsaturated fats (especially omega-6).
  • Avoid saturated fat if you are a hyper absorber or if you have bad LDL-receptor activity.
  • Explore plant based diets [low on sterols] (again if you are a hyper absorber and bad receptors).

Lp(a)

  • Type of lipoprotein related to LDL.
    • Lp(a) is a cholesterol rich LDL particle with an extra apo(a) protein added on, hence the “little a.”
  • Genetically determined.
    • Evolved for helping blood clotting in the short-term.
  • However, significantly increases cardio risks in the long-term.
    • We were designed for a different world where wounds were a greater risk than heart disease.
  • Elevated Lp(a) = increased risk of cardiovascular disease.
    • One in five people have high levels of Lp(a) (greater than 50mg/dL).
  • As high levels of Lp(a) travel through the bloodstream, it collects in the arteries, leading to gradual narrowing of the artery that can limit blood supply to the heart, brain, and kidneys as well as the legs.
    • It can increase the risk of blood clots, heart attack or stroke.
  • 2 to 3 times increased risk for heart disease when Lp(a) levels are greater than 30mg/dl, or 75 nmol/L.
  • Measurement: prefer to know the number of particles, as opposed to the amount.
    • Most “normal” lipid panels don’t include Lp(a).
  • A genetic issue.
    • Fixed at conception and cannot be confounded by environmental factors.
    • Not significantly influenced by diet or exercise.
    • Tends to minimally fluctuate around a pre-determined genetic level.

Lp(a) Details

  • apo(a) has a unique structure.
    • Contains multiple repeats of looped protein segments.
    • Resembles the kringle-4 structure of plasminogen.
  • Molecular weight of apo(a) is determined by the number of kringle-4 repeats.
  • Number of kringle-4 segment repeats accounts for the variance in Lp(a) concentrations.
  • Inverse correlation between the number of kringle-4 repeats and Lp(a) concentration:
    • The larger the molecule, the lower the concentration in the bloodstream.
    • Larger molecules take more time to be formed / folded in the liver.
    • May be degraded before they get the chance to be released from the liver (good).
    • Important to determine isoform of Lp(a).
    • May be useful to determine particle count of Lp(a).
  • apo(a) is highly homologous to plasminogen.
    • Competes with plasminogen for binding to plasminogen receptors.
    • Inhibits plasmin generation.
    • Bad: acceleration of cell growth of vascular smooth muscle cells.

Lp(a): Fixing Pathways

  • Lower synthesis
    • apo(a) is made in the liver.
    • Most promising drugs (ASO) focuses on this, but not available yet.
  • Increase clearance rate:
    • Upregulate plasminogen receptors or LDL receptors.
    • Sometimes more difficult, as LDL receptors have higher affinity for LDL clearance.
      • On Lp(a), the binding segment on apoB may be “covered up” by apo(a).

Cholesterol Lowering Drugs

  • Apheresis:
    • Blood of a person is taken out.
    • Filtered, cleared and returned to circulation.
    • Rarely resorted to.
    • Needs to be done multiple times a week.
  • Niacin (vitamin B3):
    • Lowers apoB/LDL, increases HDL, lowers Lp(a).
    • Mixed opinions, checkered trials.
    • Unclear if Niacin actually reduces mortality.
    • Side effects are many, including potential for increased insulin resistance.
  • PCSK9 Inhibitors:
    • Aimed at raising clearance rates.
    • Upregulates LDL receptors.
    • If PCSK9 enzyme is blocked (by the inhibitor drug), more LDL receptors are available to remove LDL particles.
    • Viable option.
  • ASO:
    • Antisense oligonucleotide.
    • Great potential – up to 90% reduction in Lp(a) in trials.
    • Targeted at disrupting the synthesis of apo(a) in the liver.
    • Not on the market yet.
    • Phase II trial completed successfully in November 2018.
  • CETP Inhibitors:
    • Prevent transfer of cholesterol from HDL to other lipoproteins.
    • Increases HDL, which has no proven benefit.
    • Mildly lowers apoB – not clear why – stays in body long time.
    • May not be a good option.
  • Berberine
    • Chemical found in certain plants.
    • Commonly taken for diabetes, high cholesterol, and high blood pressure.
    • Helps to lower both cholesterol and triglycerides.
    • Lowers cholesterol the same way as PCSK9 inhibitors (upregulating LDL receptors).
    • Other main action is to activate AMP-activated protein kinase, which is involved in:
      • Stimulating oxidation (breakdown) of fatty acids inside the liver.
      • Stimulating the production of ketones (breakdown products of fat), to be used for energy
      • Inhibiting the production of cholesterol and triglycerides.
      • Inhibiting lipogenesis (the creation of fat).
      • Increasing the utilization of glucose by skeletal muscle cells (thereby helping to reduce elevated blood sugar).
      • Regulating the production of insulin by beta cells in the pancreas, thus helping blood sugar control.
    • Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5839379/
    • Option as additional supplement.
  • Statins
    • Lowers amount of LDL particles.
      • By decreasing cholesterol synthesis in the liver.
    • Also lowers LDL by causing the liver to upregulate the production of LDL receptors.
      • Because the liver wants and needs more cholesterol.
      • At the same time, slight increase in level of PCSK9.
      • Protect / check against too high an increase in LDL receptors.
      • Net result: enhanced clearance of the LDL particles.
    • However, LDL receptors have a lower affinity for binding with Lp(a)
      • Mainly engaged in the removal of LDL.
    • So statins alone don’t necessarily lower Lp(a).
    • You would have to combine them with PCSK9 inhibitors (if you want to lower Lp(a).
  • Others:
    • Metformin
      • If you are insulin resistant, ie if you have high TG causing high LDL-P.
    • Aspirin
    • Testosterone
      • May play a role in regulating apo(a) synthesis in the liver; may lower Lp(a) to below threshold levels, but not any farther (limited data from studies).
    • DHEA
      • testosterone-like adrenal hormone that declines with age; moderate effect (10-15% reduction); may lead to hormonal imbalances; concern about the long-term impact on promoting cancers (limited data from studies).
    • Omega 3 fish oil
      • Perhaps by decreasing LPL-P (as it lowers TG, the “cargo”).

Leave a Reply