#22 – Tom Dayspring Part III of V: reverse cholesterol transport, CETP inhibitors, & apolipoproteins

KEYPOINTS

• 01

  Most cholesterol is made by peripheral cells, and it has to get out

  Dayspring says the liver makes only about 20% of the body's cholesterol. The rest is made by cells throughout the body. A cell that accumulates too much must export it or die. Cells push free cholesterol out through transporters such as ABCA1 to apoA-I, the HDL protein. Lipid-poor 'baby' HDL particles are especially good at picking it up. Attia says that of all seven hours with Dayspring, he learned the most from the HDL and CETP discussions.

• 02

  Reverse cholesterol transport has more than one route

  HDL can deliver cholesterol directly to the liver, small intestine, adrenal glands, ovaries or testes. It can also hand cholesterol to apoB particles via CETP (cholesteryl ester transfer protein), and the liver then clears those through LDL receptors. Red blood cells and albumin (one albumin molecule can carry up to 17 cholesterol molecules) also move cholesterol. Even excretion is leaky: the gut reabsorbs about 90–95% of bile salts.

• 03

  Remnants are cleared by apoE; LDL lingers

  As VLDL and chylomicrons lose their core triglycerides, they become remnants. Dayspring compares it to being 'a remnant of my former self' after losing an arm. Remnants carry apoE, which binds both LDL receptors and LDL-receptor-related proteins, so they are cleared quickly. LDL relies on apoB-100 alone, so it can 'hang around forever' until an LDL receptor clears it. Some people carry more apoE on their LDLs.

• 04

  ApoC-III makes particles more atherogenic

  An LDL particle that carries apoC-III is 'intensely more atherogenic' than one with apoB-100 alone, because apoC-III impairs clearance. Drugs targeting apoC-III were in development at a San Diego company. Dayspring considers triglycerides above about 130 mg/dL a sign of a problem.

• 05

  In insulin resistance, most of the added apoB comes from LDL

  When triglycerides rise, VLDL particle numbers can double or triple, for example from 30 to 90 nmol/L. Because LDL starts from a much higher base (about 1,000 rising to 3,000 in the example given), the extra 300–400 nmol/L of LDL dominates the risk. A big relative change in VLDL can be a small share of the total apoB.

• 06

  VLDL-C is a crude marker

  Dayspring once estimated VLDL remnants with VLDL cholesterol. He now calls it 'a very crude estimation that's almost useless', which he says annoys his lipid colleagues. He still tells patients to aim for VLDL-C under 15 mg/dL when nothing better is available.

• 07

  'Good cholesterol' is a misnomer

  HDL can transfer its cholesteryl ester to an LDL particle (about 95% of apoB particles are LDL). That LDL can end up in a macrophage in the artery wall. HDL particles also swap lipids with each other. Dayspring tells doctors that calling HDL-C 'good cholesterol' is 'mis-educating patients'.

• 08

  Low HDL-C is mostly a proxy for high apoB

  In the Framingham-era data, low HDL-C and high triglycerides travel with very high apoB in almost everyone not on drugs or a strict diet. Dayspring says that if those studies had adjusted for apoB or LDL particle number, which they couldn't, low HDL-C would likely disappear as an independent risk factor. Insulin-resistant patients' disease is ultimately apoB-driven.

• 09

  HDL-C doesn't tell you whether HDL is working

  Low HDL-C could mean poor pickup of cholesterol or fast delivery of it. High HDL-C could mean good pickup or a failure to drop cholesterol off. HDL particles carry about 200 identified proteins, and their protein and phospholipid signatures likely matter more than their cholesterol content. Functional HDL assays are still largely research tools.