#21 - Tom Dayspring, M.D., FACP, FNLA – Part II of V: Lipid metrics, lipid measurements, and cholesterol regulation
In this episode, Dr. Thomas Dayspring, a lipidology expert, provides a 101 on lipids and lipoproteins, discussing their structure, function, and metabolism. He and Peter Attia delve into measurement techniques like NMR, clarifying the critical distinctions between LDL-C, LDL-P, and ApoB, and emphasizing their importance for assessing cardiovascular risk.
Deep Dive Analysis
15 Topic Outline
Early Lipid Measurement and Gofman's Lipoprotein Discovery
Lipoprotein Structure, Density, and Buoyancy Explained
Apoproteins: Function, Nomenclature, and APOB's Significance
Interpreting Standard Lipid Panel Metrics
History and Limitations of LDL Cholesterol Measurement
Nuclear Magnetic Resonance (NMR) for Lipoprotein Particle Counting
LDL Cholesterol vs. LDL Particle Number (LDL-P) and ApoB for Risk
Sterol Chemistry: Cholesterol, Stanols, and Phytosterols
Cholesterol Absorption and Efflux Mechanisms in the Intestine
Transintestinal Cholesterol Efflux (TICE) Pathway
Cholesterol Synthesis Pathways: Block and Kandutsch-Russell
Brain Cholesterol Metabolism: Independent Regulation
Cellular Cholesterol Needs and Hormonal Synthesis
Cholesterol's Non-Role as an Energy Source
Acute Stress and its Impact on Lipid Profiles
10 Key Concepts
Lipoproteins
Lipoproteins are water-soluble lipid transportation vehicles, essential for circulating hydrophobic lipids in the water-based plasma. They are protein-wrapped collections of hydrophobic and amphipathic lipids.
Lipoprotein Density
The density of a lipoprotein is determined by the ratio of its lipid (fat) content versus its protein content. Particles with more lipids are more buoyant (less dense), while those with more protein are denser.
Apoprotein / Apolipoprotein
An apoprotein is a protein synthesized by a cell. Once it binds to lipids, it becomes an apolipoprotein, forming part of a lipoprotein particle and directing its specific catabolic pathway or function.
ApoB (Apolipoprotein B)
ApoB is a large, structural, non-transferable apoprotein found on chylomicrons (ApoB48) and VLDLs, IDLs, and LDLs (ApoB100). It provides structural integrity to these particles and serves as a ligand for receptors that internalize them, making it a direct measure of atherogenic particle count.
Cholesterol Ester (CE)
Cholesterol ester is a storage and transportable form of cholesterol, created when a long-chain fatty acid replaces the hydroxy group of free cholesterol. It must be de-esterified back to free cholesterol before cells can utilize it for membrane structure or hormone synthesis.
Sterol
A sterol is a molecule characterized by a four-ring structure, a carbon tail, and a hydroxy (-OH) group on the third carbon of the first ring. Cholesterol is the primary zoosterol (animal sterol) produced and utilized by humans.
Stanol
A stanol is a saturated sterol, meaning it lacks the double bond typically found at carbon 5 and 6 in the first ring of a sterol like cholesterol. Stanols, such as cholestanol, are poorly absorbed by the human intestine and are a mechanism for the body to excrete cholesterol.
Phytosterol
Phytosterols are sterols produced by plants that structurally resemble cholesterol but have slight differences. They are poorly absorbed by the human intestine and are actively evicted, suggesting that excessive absorption could lead to toxicity.
Cholesterol Homeostasis
Cholesterol homeostasis refers to the body's intricate regulatory system that balances cholesterol synthesis, absorption, influx, and efflux. This ensures that cells maintain optimal cholesterol levels for function without harmful accumulation.
Transintestinal Cholesterol Efflux (TICE)
TICE is a significant pathway for cholesterol excretion, where cholesterol is transported directly to the intestine (bypassing the liver) and then effluxed into the gut lumen to be eliminated in stool.
11 Questions Answered
Lipids, being hydrophobic, travel in the bloodstream as passengers inside water-soluble lipid transportation vehicles called lipoproteins, which are protein-wrapped collections of lipids.
The density of a lipoprotein is determined by the ratio of its lipid (fat) content to its protein content; more lipids make it more buoyant (less dense), while more protein makes it denser.
An apoprotein is the protein made by a cell, and it becomes an apolipoprotein once it binds to lipids, forming part of a lipoprotein particle.
ApoB is a non-transferable protein, with one ApoB molecule on every atherogenic lipoprotein (VLDL, IDL, LDL), making its concentration a direct measure of the number of these particles, which is a primary driver of atherosclerosis.
LDL-C measures the amount of cholesterol contained within LDL particles, while LDL-P or ApoB measures the actual number of those particles; risk for atherosclerosis follows the particle metric (LDL-P/ApoB) more closely than the cholesterol metric (LDL-C).
The Friedewald formula, which estimates VLDL cholesterol as triglycerides divided by five, becomes less accurate when triglyceride levels are elevated (above 150-200 mg/dL) because the assumed VLDL composition ratio no longer holds true.
Phytosterols are plant sterols that the human body is not designed to absorb; their presence in the bloodstream can be a biomarker for cholesterol hyperabsorption and may be more atherogenic than cholesterol itself, suggesting potential toxicity if consumed in excess.
The intestine absorbs sterols via the NPC1L1 protein (preferring cholesterol), and then uses ABCG5/G8 transporters to efflux unwanted sterols (preferring phytosterols, then stanols, then cholesterol) back into the gut lumen for excretion, or packages them into chylomicrons/HDLs for circulation.
No, cholesterol metabolism in the brain is largely independent of plasma cholesterol levels because LDL particles cannot cross the blood-brain barrier; the brain synthesizes all the cholesterol it needs locally.
No, the body does not have the enzymatic machinery to metabolize cholesterol for energy (ATP production); its primary roles are in cell membranes and as a precursor for hormones and bile acids.
During acute physiological stress, such as sepsis or trauma, lipid levels can be transiently altered, with a notable drop in HDL cholesterol due to increased demand for steroid hormone production, making measurements inaccurate for baseline risk assessment.
10 Actionable Insights
1. Demand ApoB or LDL-P Test
If your doctor reports a normal LDL cholesterol, ask for your ApoB or LDL particle count. If it hasn’t been done, demand it immediately, as these metrics are crucial for understanding your lipid-related cardiovascular risk.
2. Prioritize Particle Metrics Over Cholesterol
When assessing cardiovascular risk, understand that the risk follows particle metrics (ApoB or LDL-P) more closely than cholesterol metrics (LDL-C). To fully understand your risk, measure both to identify potential discordance.
3. Do Not Ignore Elevated LDL-P/ApoB
Ignoring an elevated LDL particle count or ApoB level is ‘playing with fire,’ as the overwhelming amount of literature indicates a significant increased risk for atherosclerotic disease over 20-30 years.
4. Avoid Phytosterol Supplements
Avoid phytosterol supplements, as evolution suggests the human body is designed not to absorb them, and there is data indicating they may be more atherogenic than cholesterol, especially for hyperabsorbers.
5. Monitor Phytosterol Levels if Supplementing
If you are supplementing with phytosterols, or if a physician prescribes them, it is crucial to monitor phytosterol levels in the bloodstream to identify if you are a ‘hyperabsorber,’ in which case supplementation should be avoided due to potential toxicity.
6. Avoid Friedewald Formula with High Triglycerides
If your triglyceride levels are above 400 mg/dL (or even 150-200 mg/dL), do not rely on the calculated LDL cholesterol (Friedewald formula) as it becomes erroneous; instead, seek a direct LDL-C measurement.
7. Avoid Lipid Profile During Acute Stress
Do not get a lipid profile during an acute physiological stress or illness (e.g., sepsis, trauma), as lipid levels will be transiently altered and will not accurately reflect your baseline risk.
8. Clarify Lipid Terminology
When discussing lipid metrics with your physician, specify ‘LDL cholesterol’ or ‘LDL particle number’ instead of just ‘LDL’ to ensure accurate communication and avoid misidentification as an ‘ignoramus’.
9. Access Lipid Particle Tests Directly
If your physician is unwilling to order an ApoB or LDL particle count, you can often obtain these assays directly through services like LabCorp in the United States without a prescription.
10. Engage with Dr. Lipid on Twitter
If you have legitimate questions about lipids, engage with Dr. Lipid (Tom Day Springs) on Twitter by asking questions or sending direct messages, as he often answers legitimate inquiries.
7 Key Quotes
Lipids, for the most part, go nowhere in the human body unless they're a passenger inside a lipoprotein.
Thomas Dayspring
Atherosclerosis is just an evidence of illegal dumping, where a lipoprotein, instead of bringing lipids to wherever it's supposed to be bringing, it was bringing sterols to the arterial wall.
Thomas Dayspring
Don't tell me the LDL is this because LDL is a low density lipoprotein. It's not a laboratory metric. You want to tell me what the LDL cholesterol is, the LDL particle number is, the lipidomics of an LDL is the LDL oxidized or not? Great.
Thomas Dayspring
The only value that calculated or directly measured LDL cholesterol brings to the table, is it's a better poor man's estimate of your LDL particle concentration than is total cholesterol.
Thomas Dayspring
If you ever go to a doctor and you're told, I'm very happy because your LDL cholesterol is normal, say, well, so am I, doc. But by the way, what was the ApoB or LDL particle count? And if the doctor didn't do it, you demand he do it instantly because otherwise you don't know your lipid-related risk.
Thomas Dayspring
Everything I've talked about cholesterol today that we're measuring in the blood has zero to do with cholesterol in the brain. Cholesterol, lipidology in the brain is might as well be in another different body.
Thomas Dayspring
The only usability of plasma measurements are as surrogates of lipoprotein defining whether you have APO-B, APO-A1 particles. And we know too many APO-B particles. You're over time at big risk, at increased risk for atherosclerotic disease or events. Otherwise, why even measuring lipids in the plasma tells you nothing.
Thomas Dayspring