Chylomicrons defined

Kane (1989)]. Chylomicron remnants are rapidly removed from plasma in a process known to be mediated by apoE (Shelburne et ai, 1980 Sherrill et al, 1980 Windier et al, 1980). The full details of this uptake process have not been completely defined. It has been postulated that the LRP receptor functions as the so-called remnant receptor (Kowal et al, 1989, 1990). In vivo evidence indicates that LRP is involved in uptake of chylomicron remnants (Hussain et al, 1991 Mahley and Hussain, 1991). In addition, LDL receptors also appear to play a role in uptake (Choi et al, 1991). Thus, at this point it appears that remnants may be cleared by two receptor systems. Therefore, in this regard, the scheme depicted in Fig. 7 is oversimplified. However, what clearly has been established is that apoE is a critical component of the chylomicron clearance process regardless of the receptor or receptors that are involved. 

Fig. 1. General oil-droplet model of lipoproteins is presented for chylomicron, very low-density lipoprotein (VLDL), low-density lipoprotein (LDL), and high-density lipoprotein (HDL) structures. Apolipoproteins in the outer phospholipid membrane, designated by letters, are defined in Table II. The major differences between the lipoproteins are the size of the neutral lipid (triglyceride and esterified cholesterol) core, liquid composition in the core, and apolipoprotein composition. (E) Triglycerides, ( Q ) phospholipids, and ( -) esterified cholesterol are shown. Although not shown, unesterified cholesterol is found predominantly in the phospholipid monolayer.

The CDC has also defined a reference method for LDL cholesterol based on the same techniques described above for HDL cholesterol. After ultracentrifugation to remove the VLDL and any chylomicrons present, the bottom fraction (d > 1.006) is subjected to precipitation by heparin and manganese as described previously. After measurement of cholesterol in the d > 1.006 fraction and in the heparin-Mn supernatant solution, LDL cholesterol is calculated by difference. It should be noted that the LDL fraction as measured by this reference method is a so-called broad-cut fraction including any IDL and Lp(a). 

Intermediate-Density (Remnant) Lipoproteins Remnant lipoproteins include the lipolytic products of catabolism of the triglyceride-rich lipoproteins, VLDL and chylomicrons, occurring in the VLDL and LDL ranges. A traditionally defined fraction at the lighter end of the LDL density range, the IDL portion comprises the 1.006 to 1.019 g/mL fraction, which is obtained by sequential ultracentrifugation for quantitation, generally in terms of cholesterol content. 

Figure 35-1. Formation and metabolism of chylomicrons. (Abbreviations used are defined in the enclosed box.)...

On the basis of the data reviewed in this chapter, it seems likely that there are functionally distinct pools of cholesterol in the intestinal epithelial cell that serve different metabolic functions. These pools are illustrated diagrammatically in the model of an epithelial cell shown in Fig. 14. Pool A is defined as having been derived largely from the uptake of luminal unesterified cholesterol (arrow 1) and serves as a major substrate for the CoA-dependent esterification reaction (arrow 2). The cholesterol esters that result from this reaction are incorporated into the hydro-phobic core of the chylomicron particle. Following cholesterol feeding there is a marked increase in apparent ACAT activity in the intestinal epithelium that seems to be related to an increase in the amount of intracellular cholesterol available to the enzyme under the in vitro conditions of the assay rather than to an increase in the... 

Terms in bold are defined P oxidation XXX chylomicron XXX apolipoprotein XXX lipoprotein XXX perilipins XXX hormone-sensitive lipase XXX free fatty acids XXX serum albumin XXX... 

With this state of uncertainty, it is not possible to define the true structural and functional role of the chylomicron protein. Chylomicrons are generally considered as a large central sphere of glycerides with small amounts of cholesterol, phospholipid, and protein loosely adsorbed on the surface, forming, according to Lindgren and Nichols (1960), small lipoprotein subunits. Aside from physical stabilization, the adsorbed components at the surface appear to impart biochemical specificity to the chylomicron particles, as indicated by Korn s studies (1955) showing that chylomicrons, and not simple fat emulsions, form an optimal substrate for the enzyme lipoprotein lipase. 

The lipoproteins present in plasma may be operationally defined according to their density, as low or very low density lipoproteins and high density lipoproteins, but other, more functional definitions may be more appropriate in connection with in vivo metabolism. Examples are the hpoprotein classes chylomicrons and chylomicron remnants. Alaupovic has suggested a classification based on the apolipoprotein composition [1]. As apolipoproteins often determine the metabolic fate of lipoprotein particles this is a logical approach. Lipoprotein particles with specific apolipoprotein compositions exist in all density fractions of human plasma, as well as plasma from a variety of animal species. 

Lipids circulate in blood as constituents of the lipoproteins or bound to albumin (free fatty acids). Electrophoretic separation of plasma proteins on paper is a relatively easy and convenient method for the semi-quantitative analysis of lipoproteins. Staining the strips with dyes which only respond to lipids reveals three well-defined bands when normal plasma or serum is analyzed. The a-lipoprotein migrates the farthest from the origin. The pre-j8, previously called the a-2-hpoprotein, and the jS-Hpoprotein, are closer to the origin. In the post-prandial normal serum, and in some hyperlipemic sera, after fasting, a fourth band can be seen at the origin. This band is due to neutral fat particles with a small protein content (i.e. chylomicron fraction). 

The anatomic sites (subcellularly) and the details of the enzymatic processes involved in the hydrolysis of chylomicron cholesteryl esters newly taken up by the liver have not been fully defined. It is clear that one of the major processes consists of receptor-mediated endocytosis of chylomicron remnants, followed by hydrolysis of cholesteryl esters and other remnant components within lysosomes. In rare genetic diseases characterized by lysosomal acid lipase deficiency (Wol-man s disease and cholesteryl ester storage disease), cholesteryl esters accumulate in liver cells and in other tissues as well [see Assmann and Frederickson (1983) for review and references]. An acid cholesteryl ester hydrolase from rat liver lysosomes has been partially purified and characterized (Brown and Sgoutas, 1980 Van Berkel etal., 1980). Enzymatic activity was found in preparations of both parenchymal and nonparenchymal liver cells (Van Berkel et al., 1980). Hydrolysis of chylomicron cholesteryl esters taken up by isolated rat hepatocytes was inhibited by chloroquine (Florin and Nilsson, 1977), an agent which inhibits the action of acid hydrolases in lysosomes. Finally, there is also evidence that the rate of cholesteryl ester hydrolysis may be limited by the rate at which internalized remnant particles are moved to the presumably lysosomal site of hydrolysis (Nilsson, 1977 Florin and Nilsson, 1977 Cooper and Yu, 1978). 

Electron microscopic studies have shown that in the liver of the rat the sinusoids are lined by a discontinuous endothelium. The cells have no well defined basement membrane and may be separated from each other by gaps of several thousand Angstrom units. When particles of smaller diameter than these gaps are introduced into the circulation they can enter the subendothelial space of Disse and come into direct contact with the microvilli on the surface of the hepatic parenchymal cells (Bennet et al. 1959). Following the intravenous injection of chyle, chylomicrons could be seen within the lumen of hepatic sinusoids, within gaps of their endothelial lining and within the subendothelial space (French 1963). 

All lipoprotein classes contain proteins, free and esterified cholesterol, TG and phospholipids however, the relative proportion of any component varies so that protein and phospholipid percentages are higher in a-lipoproteins (high-density lipoproteins) and lower in chylomicrons. The reverse is true for TG, while cholesterol circulates mainly as -lipoprotein (low-density lipoprotein). Since lipids circulate as lipoproteins, hyperlipaemias can be more properly defined as hyper-lipoproteinaemias. A classification of human hyperlipoproteinaemias based on chemical determination of plasma lipid classes as well as on paper electrophoretic separation of plasma lipoproteins has been proposed... 

A change in the opposite direction occurred in the distribution of the label between esterified and free cholesterol when the uptake of cholesterol ester-labeled chylomicrons by the liver was studied (O. Stein et al., 1969). Since both the lability toward dehydrating agents and the ultrastructural localization of free and esterified cholesterol may differ considerably, it is important to determine chemically and define the nature of the compound at the time of its visualization. 

---