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Peter Attia MD#21 – Tom Dayspring, M.D., FACP, FNLA – Part II of V: Lipid metrics and cholesterol regulation
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CHAPTERS
- 0:04 – 6:15
Lipids Travel in Lipoproteins: Gofman and the Ultracentrifuge
Peter Attia asks about early total cholesterol assays, and Tom Dayspring explains that Gofman's ultracentrifuge work showed lipids must travel inside water-soluble lipoproteins. Dayspring argues that atherosclerosis reflects lipoproteins delivering sterols to the arterial wall.
- •Cholesterol could be measured long before Gofman's work
- •Lipids are hydrophobic and need a lipoprotein or albumin to circulate in plasma
- •Gofman, a physicist, saw lipoproteins in the centrifuge
- •Dayspring jokes that atherosclerosis is evidence of illegal dumping by lipoproteins
- •A sphere is the most efficient transport shape
- 6:15 – 15:58
Density, Size and ApoB: Why Particles Differ
The discussion explains what lipoprotein density means and how the lipid-to-protein ratio determines buoyancy. Dayspring describes the separate lineages of chylomicrons, VLDL and LDL versus HDL, and why apoB is the non-transferable structural protein on atherogenic particles.
- •Density reflects lipid content versus protein content
- •Small LDL is redundant with dense LDL; small LDLs mean a high particle count
- •ApoB is never lost and is the ligand for receptors such as the LDL receptor
- •Definitions of apoprotein, apolipoprotein and lipoprotein
- •Later researchers named and characterized the apoproteins
- 15:58 – 28:59
Reading a Lipid Panel: Total Cholesterol, HDL-C and Friedewald LDL-C
Attia asks what the numbers on a standard blood test mean, and Dayspring insists on precise labeling of lipid metrics. They cover apoB-48 versus apoB-100, how total cholesterol is measured, and how LDL-C is calculated by the Friedewald formula and when it fails.
- •Labels should be LDL cholesterol, not LDL
- •ApoB-48 marks intestinal origin and apoB-100 hepatic origin
- •Total cholesterol is a poor man's apoB
- •Friedewald estimates LDL-C using triglycerides divided by five
- •The calculation falters at higher triglycerides, where direct LDL-C is used
- 28:59 – 36:05
NMR, LDL-P and ApoB: Particle Number Versus Cholesterol
They discuss how Jim Otvos used NMR to count lipoprotein particles and why apoB and LDL-P are particle metrics. Dayspring explains concordance and discordance and says risk follows particle number more than cholesterol content.
- •NMR derives particle numbers from lipid spectral signals
- •ApoB tracks LDL particle number since most apoB particles are LDLs
- •Concordant and discordant metrics
- •Risk follows particle metrics in virtually every trial looked at
- •Both speakers urge patients to ask for apoB or LDL-P
- 36:05 – 39:53
Physician Resistance and Denial of Particle Metrics
Attia and Dayspring discuss the frustration patients face when asking doctors for apoB or LDL-P. Dayspring cites guidelines and payers as obstacles and criticizes internet deniers of particle concentration.
- •Patients may have to argue with their doctors for these tests
- •Attia lists LDL-P or apoB among the five most important metrics
- •Dayspring blames guidelines and third-party payers for the lag
- •Some online voices ignore particle counts
- •Dayspring says ignoring elevated apoB is playing with fire
- 39:53 – 54:09
Sterol Chemistry: Sterols, Esters, Stanols and Phytosterols
Attia asks Dayspring to clarify sterol terminology, and Dayspring walks through cholesterol's ring structure, esterification, and how stanols differ from sterols. They then turn to plant sterols and why the body has evolved to exclude them.
- •Structure of cholesterol, including the hydroxy group and tail
- •Free cholesterol versus cholesterol ester
- •Stanols are saturated sterols that are not reabsorbed; gut microbes convert cholesterol to coprostanol
- •Phytosterols are not absorbed under normal evolution-driven handling
- •Attia's disagreement with a physician over phytosterol supplements
- 54:09 – 1:04:09
Intestinal Absorption: NPC1L1, ABCG5/G8, ACAT and TICE
Using the ticket taker and bouncer analogy, the speakers explain how NPC1L1 and ABCG5/G8 regulate sterol absorption and why hyperabsorbers arise. Dayspring also describes ACAT, ABCA1 and transintestinal cholesterol efflux as a major route for removing cholesterol.
- •NPC1L1 admits sterols, preferring cholesterol
- •ABCG5/G8 export phytosterols first, then stanols, then cholesterol
- •Loss of ABCG5/G8 function can cause hyperabsorption
- •ACAT esterifies cholesterol but not phytosterols well
- •TICE may account for roughly 20% to 60% of cholesterol removal
- 1:04:09 – 1:07:40
Peer Review and Staying Current with Lipid Literature
A tangent begins when Attia asks how many articles Dayspring reviews each year. They discuss his role as associate editor and reviewer, his current job, and how people can follow his paper summaries.
- •Dayspring is an associate editor and reviewer, about 50 papers a year
- •His role as scientific academic advisor lets him spend time reading
- •Attia values Dayspring's short summaries of papers
- •Copyright limits sharing PDFs; Twitter is the best route
- 1:07:40 – 1:13:51
Cholesterol Synthesis Pathways: Bloch and Kandutsch-Russell
Attia returns to the synthetic side of cholesterol regulation. Dayspring describes the multi-step synthesis from acetyl-CoA through lanosterol and its two branches, including desmosterol and lathosterol, plus the enzyme and disease implications.
- •Synthesis takes 20 to 30 steps starting from acetyl-CoA
- •Lanosterol is the first sterol in the chain
- •The Bloch pathway passes through desmosterol
- •The Kandutsch-Russell pathway ends via lathosterol
- •Desmosterolosis results from a deficiency of the enzyme that saturates desmosterol
- 1:13:51 – 1:15:22
Brain Cholesterol Is Separate from Plasma Cholesterol
Dayspring explains that the cholesterol measured in blood has nothing to do with brain cholesterol, which the brain makes itself. Attia notes that LDL particles cannot cross the blood-brain barrier, and apoE transports sterols in the brain.
- •The brain makes all the cholesterol it needs
- •LDL particles do not reach the brain
- •Only inconsequential HDL cholesterol may enter
- •ApoE is the brain's lipid transporter
- •Attia says they will return to the topic
- 1:15:22 – 1:18:49
Uses of Cholesterol: Membranes, Hormones, Bile Acids and Not Energy
The speakers discuss what cells do with cholesterol: build membranes, make steroid hormones, and make bile acids, but never burn it for energy. Attia offers a hypothesis about why cholesterol cannot be metabolized for fuel, tied to starvation and ketosis.
- •Cells use cholesterol for cell and organelle membranes
- •Steroidogenic tissues and hepatocytes can convert it into hormones or bile acids
- •Cholesterol cannot be metabolized for ATP
- •Attia's guess is that evolution protected membranes and hormones during fasting
- •Cholesterol can only be converted in specific tissues or excreted
- 1:18:49 – 1:27:02
Cellular Cholesterol Homeostasis, Stress and HDL
The conversation turns to why plasma cholesterol says little about cellular cholesterol and how cells regulate synthesis, influx and efflux. Attia recalls HDL falling in ICU patients with SIRS, and Dayspring describes HDL as a reservoir supplying steroidogenic tissues and adipocytes as a major storage site.
- •Plasma measurements are a snapshot that says nothing about flux or what happens inside cells
- •Cells must keep cholesterol between depletion and crystallization
- •Attia observed HDL cholesterol dropping in SIRS patients
- •Steroidogenic tissues may upregulate LDL receptors under stress
- •Adipocytes store large amounts of cholesterol and efflux it to HDL via ABCA1
