Chylomicron remnant particles

The remarkable rapidity and specificity of uptake of the chylomicron remnant particles is believed to be highly dependent on their acquisition of apo E in the bloodstream (ref. 664,665) the critical role played by apo E in directing the clearance of chylomicron remnants from the (blood) plasma has been well... 

The chylomicron remnant particles themselves, derived from lipolysis of the larger chylomicrons (cf. above), contain the residual triglyceride and all of the cholesterol and cholesterol ester from the original chylomicrons. This lipid composition of the chylomicron remnant particles is similar to the above-described lipid composition of both LDL particles (cf. Section 14.1) and LCM (cf. Section 12.1). Based upon this molecular similarity, it appears reasonable to expect that injected LCM could also readily bind apo E (i.e., as an alternative to apo B) in the bloodstream. In this case, the proposed LCM binding of apo E should influence the subsequent biodistribution of those LCM via two endocytic pathways specifically, one pathway mediated by the LDL receptor (a.k.a. apo B,E receptor ) (cf. Section 14.1) and the other pathway mediated by the LRP, since both receptor types have a high affinity for apo E (cf. above). 

If the remarkable rapidity and specificity of uptake of the chylomicron remnant particles by these two different endocytic pathways reflects a similar uptake pattern for LCM as proposed, then one would probably expect a large portion of the LCM size distribution to be in the same diameter range as found with chylomicron remnants. The remnant particles are of particular interest because their size distribution is known (cf. below) to display both a wider range (i.e., more polydispersity) and larger sizes than either LDL or modified LDL particles accordingly, this polydispersity provides more information about the size constraints or limits imposed by the endocytic pathways involved in the active uptake of chylomicron remnant particles and probably also of LCM. The diameter range for the native chylomicron remnants has already been determined by other investigators, from in vivo and in... 

Atherosclerosis and Plasma Lipids - Lipoprotein lipases play a critical role in the metabolism of lipoproteins and thus may be involved in athero-genesis. Hypercholesterolemia in the cholesterol-fed rabbit was attributed to the accumulation of chylomicron remnants, which may be formed on the aorta wall by lipoprotein lipase and deposited in the deep layers of the arterial wall without prior release into the blood stream.13 On this basis, cholesterol-rich lipoproteins in plasma may be the product rather than the cause of the atherogenic process. However, the defect in Type III hyperlipoproteinemia (broad- disease) may be ineffective removal of chylomicron remnant particles from the arterial wall,11 due to a failure of the liver to recognize such particles.15... 

The best-known effect of APOE is the regulation of lipid metabolism (see Fig. 10.13). APOE is a constituent of TG-rich chylomicrons, VLDL particles and their remnants, and a subclass of HDL. In addition to its role in the transport of cholesterol and the metabolism of lipoprotein particles, APOE can be involved in many other physiological and pathological processes, including immunoregu-lation, nerve regeneration, activation of lipolytic enzymes (hepatic lipase, lipoprotein lipase, lecithin cholesterol acyltransferase), ligand for several cell receptors, neuronal homeostasis, and tissue repair (488,490). APOE is essential... 

The rationale for this type of contrast agent is to use the endogenous metabolic pathway of lipid metabolism in the liver for the transport of iodinated substances. Chylomicron remnants are naturally occurring lipoproteins in the blood that are responsible for the transport of lipids into the liver. Three different mechanisms for this transport are discussed direct uptake by the low-density lipoprotein receptor transport to the low-density lipoprotein receptor-related protein (LRP) mediated by heparan sulfate proteoglycan (HSPG) or direct HSPG-LRP uptake and direct HSPG uptake. One of the prerequisites for particles to be transported by these mechanisms is a mean diameter of less than 100-300 run. 

Lipoprotein metabolism. Entero-cytes release absorbed lipids in the form of triglyceride-rich chylomicrons. Bypassing the liver, these enter the circulation mainly via the lymph and are hydrolyzed by extrahepatic endothelial lipoprotein lipases to liberate fatty acids. The remnant particles move on into liver cells and supply these with cholesterol of dietary origin. 

Triglycerides are removed in extrahepatic tissues through a pathway shared with VLDL that involves hydrolysis by the lipoprotein lipase (LPL) system. Decrease in particle diameter occurs as triglycerides are depleted. Surface lipids and small apoproteins are transferred to HDL. The resultant chylomicron remnants are taken up by receptor-mediated endocytosis into hepatocytes. 

HDL is a reservoir of apolipoproteins HDL particles serve as a circulating reservoir of apo C-ll (the apolipoprotein that is transferred to VLDL and chylomicrons, and is an activator of lipoprotein lipase), and apo E (the apolipoprotein required for the receptor-mediated endocytosis of IDLs and chylomicron remnants). 

The metabolism of cholesterol in mammals is extremely complex. A summary sketch (fig. 20.24) helps to draw the major metabolic interrelationships together. Cholesterol is biosynthesized from acetate largely in the liver (fig. 20.24a) or taken in through the diet (fig. 20.24b). From the intestine, dietary cholesterol is secreted into the plasma mainly as a component of chylomicrons. The triacylglycerol components of chylomicrons are quickly degraded by lipoprotein lipase, and the remnant particles are removed by the liver. Apoproteins and lipid components of the chylomicrons and remnants appear to exchange with HDL. Cholesterol made in the liver (fig. 20.24a) has several alternative fates. It can be (1) secreted into plasma as a component of VLDL,... 

Reductions in VLDL cholesterol, LDL cholesterol, and chylomicrons may contribute to a reduction in cardiac complications. Pioglitazone reduced both lipoprotein(a) and the remnant particles (cholesterol-rich particles after the release of triglycerides from the chylomicrons), whereas troglitazone caused increases in lipoprotein(a) (86). 

LRP is a member of the LDL receptor gene family (ref. 649) and, like the LDL receptor, performs an essential role in the removal of certain lipoprotein particles from the bloodstream. As Heeren et al. (ref. 650) explain, triglycerides are transported mainly by two distinct classes of lipoproteins, the chylomicrons and the very-low-density lipoproteins (VLDL). After assembly in the intestine, chylomicrons are carried via lymph into the bloodstream, where they are transformed at the endothelial surface to remnant lipoproteins through the catalytic action of lipoprotein lipase (for review, see ref. 651,652). After lipolysis, the lipoprotein lipase remains associated with the chylomicron remnants and, in conjunction with apolipoprotein E (apo E) (ref. 653-655), facilitates their clearance by the liver into hepatocytes (ref. 656) via LDL receptors and the LRP (ref. 657-660). (The essential role for both receptors in chylomicron remnant removal in vivo has been demonstrated in gene knockout and gene transfer experiments (ref. 661,662 for review, see ref. 663).)... 

The apoproteins of HDL are secreted by the liver and intestine. Much of the lipid comes from the surface monolayers of chylomicrons and VLDL during lipolysis. HDL also acquire cholesterol from peripheral tissues in a pathway that protects the cholesterol homeostasis of cells. In this process, free cholesterol is transported from the cell membrane by a transporter protein, ABCA1, acquired by a small particle termed prebeta-1 HDL, and then esterified by lecithin cholesterol acyltransferase (LCAT), leading to the formation of larger HDL species. The cholesteryl esters are transferred to VLDL, IDL, LDL, and chylomicron remnants with the aid of cholesteryl ester transfer protein (CETP). Much of the cholesteryl ester thus transferred is ultimately delivered to the liver by endocytosis of the acceptor lipoproteins. HDL can also deliver cholesteryl esters directly to the liver via a docking receptor (scavenger receptor, SR-BI) that does not endocytose the lipoproteins. 

The WHHL model has stimulated major advances in our understanding of apoB receptors (G22). In particular, it has allowed a clear differentiation of two kinds of hepatic receptors one involved in the uptake of chylomicron remnants, recognizing (it is thought) apoE when in a particle containing apoB-48, and the other involved in the hepatic uptake of apoB-100-contain-ing VLDL, IDL, and LDL particles. The apoB-100 receptors, which also have an affinity for apoE and are referred to in this review as apoB-100, E receptors, are found in many extrahepatic cells. The WHHL rabbit is deficient in apoB-100, E receptors, but not in those receptors responsible for chylomicron clearance. 

As chylomicron triglyceride is hydrolyzed by lipoprotein lipase in the plasma compartment, the chylomicron shrinks and loses redundant surface material, including phospholipid and apolipoproteins. ApoC is lost, the particle apoE apoC ratio rises, and the apoB-48 remains with the particle. The remnant finally is taken up by a specific hepatic receptor, in a process that appears to be dependent upon the content of both apoE and apoC of the remnant particle. The uptake of apoE-containing remnant particles is discussed in Section 4,7.4. 

Macrophages appear to do more than simply bind and take up remnant particles. Cultured macrophages secrete lipoprotein lipase into the culture medium (C6, K12, M7, W3), and the consequent depletion of chylomicron triglyceride appears to accelerate the uptake of chylomicron remnants and the accumulation of eholesteryl esters by macrophages (010). Macrophages also can produce apoE (B17) perhaps this may be a mechanism for removing cholesterol from a cholesterol-loaded cell. 

Lipoprotein lipase (EC 3.1.1.34) is an enzyme or group of enzymes which catalyze the hydrolysis of the 1(3) ester bond(s) of triacylglycerols and the 1 ester bond of phospholipids. The enzyme plays a central role in lipoprotein metabolism, being responsible in particular for the hydrolysis of chylomicron and VLDL triglycerides and the formation of remnant particles from these lipoproteins. There have been reviews of this enzyme [e.g., (N9, Ql)] and lipoprotein lipase will not be discussed in detail in this review. Familial lipoprotein lipase deficiency and related disorders of chylomicron metabolism have also been reviewed (B58, N8) and will not be discussed in detail. 

Vitamin E, like neutral lipids, requires apoB lipoproteins at every stage of its transport (Fig. 27-2). Dietary vitamin E becomes emulsified in micelles produced during the digestive phase of lipid absorption and permeates the intestinal epithelium, similar to fatty acids and cholesterol. Uptake of vitamin E by enterocytes appears to be concentration dependent. Within intestinal cells, vitamin E is packaged into chylomicrons and secreted into lymph. During blood circulation of chylomicrons, some vitamin E may be released to the tissues as a consequence of partial lipolysis of these particles by endothelial cell-anchored lipoprotein lipase. The rest remains associated with chylomicron remnants. Remnant particles are mainly endocy-tosed by the liver and degraded, resulting in the release of fat-soluble vitamins. 

Cholesterol is found in all lipoprotein particles but is relatively concentrated in LDL and HDL, whereas triglycerides are relatively concentrated in chylomicrons and VLDL. Heart disease appears to correlate with increased LDL and decreased HDL. Elevated HDL generally is a favorable finding, as HDL shunts excess cholesterol back to the liver (via LDL remnant particles) where it can be excreted. Chylomicrons, VLDL, and LDL, on the other hand, carry triglycerides and cholesterol to the periphery (fig. 6.4). The more significant clinical conditions involve elevation of cholesterol, triglycerides, VLDL, LDL, and/or chylomicrons, rather than HDL. 

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