The chylomicron: relationship to atherosclerosis

Abstract

The B-containing lipoproteins are the transporters of cholesterol, and the evidence suggests that the apo B48-containing postprandial chylomicron particles and the triglyceride-rich very low density lipoprotein (VLDL) particles play an important part in the development of the plaque both directly and indirectly by their impact on LDL composition. The ratio of dietary to synthesised cholesterol is variable but tightly regulated: hence intervention with diet at best reduces serum cholesterol by <20% andusually <10%. Statins are the mainstay of cholesterol reduction therapy, but they increase cholesterol absorption, an example of the relationship between synthesis and absorption. Inhibition of cholesterol absorption with Ezetimibe, an inhibitor of Niemann Pick C1-like 1 (NPC1-L1), the major regulator of cholesterol absorption, increases cholesterol synthesis and hence the value of adding an inhibitor of cholesterol absorption to an inhibitor of cholesterol synthesis. Apo B48, the structural protein of the chylomicron particle, is synthesised in abundance so that the release of these particles is dependent on the amount of cholesterol and triglyceride available in the intestine. This paper will discuss cholesterol absorption and synthesis, chylomicron formation, and the effect of postprandial lipoproteins on factors involved in atherosclerosis.

Figure 1

chylomicron synthesis. Dietary triglyceride, phospholipid, and cholesterol, together with intestinally synthesized cholesterol (for which 3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase is the rate-limiting enzyme) and recycled biliary cholesterol together with intestinally derived ApoB48 are assembled under the influence of microsomal triglyceride transfer protein (MTP) to form the chylomicron. Prior to incorporation into the chylomicron, cholesterol is esterified by acylcoenzyme A:cholesterol acyltransferase (ACAT) and the triglycerides are reassembled from fatty acids with acylcoenzyme-A-diacylglycerol acyltransferase (DGAT) catalysing the rate-limiting step. The cholesterol is transferred across the membrane by Niemann Pick C1 like-1 and some is reexcreted back into the intestinal lumen by the action of ATP-binding cassette proteins (ABC)G5 and -G8. The particle is assembled under the regulation of microsomal triglyceride transfer protein and delivered to the lymphatics.

Figure 2

Chylomicron clearance. The chylomicron acquires apo E and apo C111 in the circulation, and most of the triglyceride is hydrolised by lipoprotein lipase (LPL) prior to it being cleared by the low density lipoprotein (LDL) B/E receptor or the LDL receptor-related protein (LRP) receptor in the liver. GPIHB also plays a smaller part in uptake of chylomicron remnants by the liver capillaries.

Figure 3

The chylomicron and atherosclerosis. The atherosclerotic plaque is composed of a lipid-rich core containing cholesterol and necrotic tissue and is covered by a fibrous smooth muscle cell cap. Low density lipoprotein (LDL) is the major contributor to plaque cholesterol, but chylomicron remnants are also taken up into the subendothelial space, and because of the rapid turnover of chylomicrons the amount of cholesterol they can deliver to the plaque is not reflected in serum chylomicron cholesterol. Chylomicrons are delipidated by lipoprotein lipase on the artery wall. They are attached to the endothelium by high-density lipoprotein-binding protein 1 (GPIHBP1) and heparin sulphate proteoglycans (HPSG) which facilitate their uptake into the subendothelial space. Chylomicron remnants become trapped in the artery wall and disintegrate to contribute cholesterol to the lipid-rich core.