Chylomicron cholesteryl ester metabolism

Much information is available about the metabolism of chylomicron cholesteryl esters taken up by the liver in association with the chylomicron remnant. This information may be relevant to the issue of chylomicron retinyl ester metabolism in the liver, about which much less direct information is on hand. Hepatic uptake of chylomicron cholesteryl esters occurs without hydrolysis of the cholesteryl esters (Goodman, 1965 (Juarfordt and Goodman, 1967 Stein et al., 1969). In studies with chylomicrons containing doubly labeled cholesteryl esters injected intravenously into rats, Quarfordt and Goodman (1967) observed that 80-90% of the chylomicron cholesteryl esters were removed by the liver without hydrolysis. In the liver, the newly absorbed cholesteryl esters underwent slow but extensive hydrolysis, to the extent of about 60% after 1 h and about 85-90% after 3.5 h. Subsequent to hydrolysis, most of the labeled free cholesterol slowly left the liver and was extensively redistributed in die body. Thus, 24 h later, only 20-28% of the labeled cholesterol found in the entire animal body was present in the liver. Since newly absorbed retinol, which is retained in the liver, is only mobilized slowly (see below), it is clear that following ester hydrolysis the hepatic metabolism of chylomicron cholesterol and retinol diverge in a major way. 

On the other hand, there are other processes that may participate as well, to some extent, in the initial metabolism and hydrolysis of chylomicron cholesteryl esters in the liver. Liver homogenates and homogenate fractions display cholesteryl ester hydrolase activity at neutral pH, and the enzyme(s) responsible for such activity have been partially purified and characterized (Deykin and Goodman, 1962 Stein et al., 1969 Tuhackova et al., 1980). It is possible that some uptake of cholesteryl esters can occur without uptake of the entire remnant particle [see, e.g., Chajek-Shaul et al. (I981a,b) for such evidence in other tissues]. It is also possible that dissociation of the constituents of the remnant can occur to some extent, permitting cholesteryl ester hydrolysis to take place before remnants are delivered to lysosomes. The extent to which these alternative processes might occur in normal physiology is not known. 

Chylomicron remnants are taken up by the liver by receptor-mediated endocytosis, and the cholesteryl esters and triacylglycerols are hydrolyzed and metabolized. Uptake is mediated by a receptor specific for apo E (Figure 25-3), and both the LDL (apo B-lOO, E) receptor and the LRP (LDL receptor-related protein)... 

Figure 25-3. Metabolic fate of chylomicrons. (A, apolipoprotein A B-48, apolipoprotein B-48 , apolipoprotein C E, apolipoprotein E HDL, high-density lipoprotein TG, triacylgiycerol C, cholesterol and cholesteryl ester P, phospholipid HL, hepatic lipase LRP, LDL receptor-reiated protein.) Only the predominant lipids are shown.

Figure 25-5. Metabolism of high-density lipoprotein (HDL) in reverse cholesteroi transport. (LCAT, lecithinxholesterol acyltransferase C, cholesterol CE, cholesteryl ester PL, phospholipid A-l, apolipoprotein A-l SR-Bl, scavenger receptor B1 ABC-1, ATP binding cassette transporter 1.) Prep-HDL, HDLj, HDL3—see Table 25-1. Surplus surface constituents from the action of lipoprotein lipase on chylomicrons and VLDL are another source of preP-HDL. Hepatic lipase activity is increased by androgens and decreased by estrogens, which may account for higher concentrations of plasma HDLj in women.

Lipoproteins. A lipoprotein is an endogenous macromolecule consisting of an inner apolar core of cholesteryl esters and triglycerides surrounded by a monolayer of phospholipid embedded with cholesterol and apoproteins. The functions of lipoproteins are to transport lipids and to mediate lipid metabolism. There are four main types of lipoproteins (classified based on their flotation rates in salt solutions) chylomicrons, very-low-density lipoprotein (VLDL), low-density lipoprotein (LDL), and high-density lipoprotein (HDL). These differ in size, molecular weight, and density and have different lipid, protein, and apoprotein compositions (Table 11). The apoproteins are important determinants in the metabolism of lipoproteins—they serve as ligands for lipoprotein receptors and as mediators in lipoproteins interconversion by enzymes. 

Fig. 5.2.1 The major metabolic pathways of the lipoprotein metabolism are shown. Chylomicrons (Chylo) are secreted from the intestine and are metabolized by lipoprotein lipase (LPL) before the remnants are taken up by the liver. The liver secretes very-low-density lipoproteins (VLDL) to distribute lipids to the periphery. These VLDL are hydrolyzed by LPL and hepatic lipase (HL) to result in intermediate-density lipoproteins (IDL) and low-density lipoproteins (LDL), respectively, which then is cleared from the blood by the LDL receptor (LDLR). The liver and the intestine secrete apolipoprotein AI, which forms pre-jS-high-density lipoproteins (pre-jl-HDL) in blood. These pre-/ -HDL accept phospholipids and cholesterol from hepatic and peripheral cells through the activity of the ATP binding cassette transporter Al. Subsequent cholesterol esterification by lecithinxholesterol acyltransferase (LCAT) and transfer of phospholipids by phospholipid transfer protein (PLTP) transform the nascent discoidal high-density lipoproteins (HDL disc) into a spherical particle and increase the size to HDL2. For the elimination of cholesterol from HDL, two possible pathways exist (1) direct hepatic uptake of lipids through scavenger receptor B1 (SR-BI) and HL, and (2) cholesteryl ester transfer protein (CfiTP)-mediated transfer of cholesterol-esters from HDL2 to chylomicrons, and VLDL and hepatic uptake of the lipids via the LDLR pathway...

Metabolism of chylomicrons. CM = chylomicron TG = triacylglycerol C = cholesterol CE = cholesteryl esters. Apo B-48, apo C-ll, and apo E are apolipoproteins found as specific components of plasma lipoproteins. 

Abnormal lipoproteins are produced under various metabolic conditions. P-VLDL, a triglyceride-depleted, cholesterol-enriched form of VLDL, accumulates in the plasma of cholesterol-fed animals [13,14] or of humans with type III hyperlipoproteinemia [15]. In patients with this disease, the accumulation of j8-VLDL is believed to be due to incomplete clearance of chylomicron remnants by the liver. Slow turnover of remnants allows them to accumulate cholesteryl esters and thus to evolve into j8-VLDL particles [16,17]. -VLDL (density <1.006 g/ml, j8-electro-phoretic mobility) contain both apo-B and apo-E and may play a significant role in the formation of atherosclerotic foam cells [18]. 

Fig. 1. Simplified schematic summary of the essential pathways for receptor-mediated human lipoprotein metabolism. The liver is the crossing point between the exogenous pathway (left-hand side), which deals with dietary lipids, and the endogenous pathway (right-hand side) that starts with the hepatic synthesis of VLDL. The endogenous metabolic branch starts with the production of chylomicrons (CM) in the intestine, which are converted to chylomicron remnants (CMR). Very-low-density lipoprotein particles (VLDL) are lipolyzed to LDL particles, which bind to the LDL receptor. IDL, intermediate-density lipoproteins LDL, low-density lipoproteins HDL, high-density lipoproteins LCAT, lecithinxholesterol acyltransferase CETP, cholesteryl ester transfer protein A, LDL receptor-related protein (LRPl) and W, LDL receptor. Lipolysis denotes lipoprotein lipase-catalyzed triacylglycerol lipolysis in the capillary bed.

T. G. Redgrave, Formation of cholesteryl ester-rich particulate lipid during metabolism of chylomicrons, J.Clin.Invest., 49 465-471 (1970). 

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