Putting cholesterol in its place: apoE and reverse cholesterol transport

Abstract

To avoid toxic overload of cholesterol in peripheral cells, the reverse cholesterol transport pathway directs excess cholesterol through HDL acceptors to the liver for elimination. In this issue of the JCI, a study by Matsuura et al. reveals new features of this pathway, including the importance of the ATP-binding cassette transporter G1 in macrophages and apoE in cholesteryl efflux from cells to cholesterol ester-rich (CE-rich) HDL(2) acceptors (see the related article beginning on page 1435). One proposal for boosting reverse cholesterol transport has been to elevate plasma HDL levels by inhibiting CE transfer protein (CETP), which transfers CE from HDL to lower-density lipoproteins. However, there has been concern that large, CE-rich HDL(2) generated by CETP inhibition might impair reverse cholesterol transport. ApoE uniquely facilitates reverse cholesterol transport by allowing CE-rich core expansion in HDL. In lower species, these large HDLs are not atherogenic. Thus, CETP might not be essential for reverse cholesterol transport in humans, raising hope of using a CETP inhibitor to elevate HDL levels.

Figure 1. Role of HDL in the redistribution of lipids from cells with excess cholesterol (e.g., macrophages) to cells requiring cholesterol or to the liver for excretion.

HDL precursors (pre-β HDL) are produced by the liver and intestine (apoA-I/PL/FC) or derived from surface material from chylomicrons after lipolysis (a, b, c). Pre-β HDL, HDL₃, and HDL₂ can accept cholesterol for reverse cholesterol transport. ApoE allows HDL₂ particles to expand by enrichment with CE of the core after LCAT converts free cholesterol to CE. Larger HDL-with apoE (HDL₂ or HDL₁) can deliver cholesterol to the liver directly via the LDL receptor. FC, free cholesterol; HDL-E, HDL-with apoE; LDLR, LDL receptor; PL, phospholipid; SR-BI, class B, type I scavenger receptor; Tg, triglyceride.

Figure 2. Based on x-ray crystallographic data, apoE is envisioned to form 2 circular horseshoe-shaped bands around a spherical phospholipid particle.

Left: The light yellow core in the center represents the phospholipid hydrophobic core containing the fatty acyl chains; the outer light purple ring represents the phospholipid polar head groups. ApoE primarily interacts with the polar head groups, not the core acyl chains. Thus, apoE on a particle is uniquely capable of facilitating core expansion and accommodating increased CE content following LCAT activity. Right: Cross section of a region of the particle showing the relationship of the 2 apoE helices to the surface phospholipid head groups and core acyl chains.