Cholesteryl esters metabolism

It is, of course, also possible that the esterified cholesterol formed in HDL may be removed from plasma by some process other than uptake of the whole HDL particle or LTP-I-mediated transfer to other lipoprotein particles, but this possibility has not been fully investigated. Some evidence that there may be other pathways than these for the removal from plasma of HDL esterified cholesterol comes from the studies of Class et al. (G5, G6), who showed that cholesteryl ether incorporated in rat HDL as a tracer for cholesteryl ester was taken up in vivo by the rat liver (and by other organs) fester than apoA-I tracer (see Section 4.1.2). These studies are complicated by the relatively high concentration of apoE in rat HDL (compared, for instance, to man) and the unknown effect of apoE on HDL cholesteryl ester metabolism in the rat. Further studies on the removal of esterified cholester-... 

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. 

Familial LCAT deficiency, an inborn error of metabolism that affects the levels of plasma cholesteryl esters, was recently discovered in Scandinavia (G7, G8, G9, GIO, Gll, N4). Patients with this disease have... 

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. 

Shinohara E, Yamashita S, Kihara S, Hirano K, Ishigami M, Arai T, Nozaki S, Kameda-Takemura K, Kawata S, Matsuzawa Y. Interferon alpha induces disorder of lipid metabolism by lowering postheparin lipases and cholesteryl ester transfer protein activities in patients with chronic hepatitis C. Hepatology 1997 25(6) 1502-6. 

In addition to the studies of clinical biological changes in lipid profile levels in patients with major depression, the mechanism of lipid metabolism should be noted and discussed [133], In past studies, the main plasma lipid transport forms have been free fatty acids, triglycerides, and cholesteryl esters. 

The search for intestinal cholesterol transporters extended for many years, beginning with a debate about whether or not it was even a protein-facilitated process (4, 5). The pancreatic enzyme carboxyl ester lipase (CEL, also called cholesterol esterase) was believed to be important to this process (6,7) and several companies devoted considerable resources to the development and testing of compounds to inhibit CEL, with mixed results (8-10). These efforts were abandoned in the mid-1990s, however, after studies with gene-knockout mice demonstrated that the enzyme was important only for absorption of cholesteryl ester (11, 12), which is a minor component of dietary cholesterol and is present at very low levels in bile. Interestingly, CEL is also found in liver where it has been shown to affect HDL metabolism (13). Thus, it may ultimately play an important role in cholesterol metabolism and may yet prove to be a useful drug target for CVD treatment (Camarota and Howies, unpublished). 

KR Marotti, CK Castle, RW Murray, EF Rehberg, HG Polites, GW Melchior. The role of cholesteryl ester transfer protein in primate apolipoprotein A-I metabolism. Insights from studies with transgenic mice. Arterioscler Thromb 12 736-744, 1992. 

FIG. 1 Schematic diagram of cholesterol transport in the tissues, with sites of action of the main drug affecting lipoprotein metabolism (C = cholesterol CE = cholesteryl ester TG = triglycerides MV A = mevalonate HMG-CoA reductase = 3-hydroxy-3-methyl-glutaryl-CoA reductase YLDL = very low density lipoproteins LDL = low density lipoproteins HDL = high density lipoproteins). (Reprinted from Rang et al (1999), with permission from Elsevier Science.)... 

Figure 5.6 General scheme of lipoprotein metabolism. Triacylglycerols and cholesterol are exported from the liver in VLDLs, containing apolipoprotein B-lOO they further acquire apo-C-I, II, III and apo-E from circulating HDL. Apo-C-II activates lipoprotein lipase to remove fatty acids from VLDLs. As triacylglycerols are removed, VLDLs transform to IDEs and finally LDLs. LDLs are the main vehicle for transfer of cholesterol to the tissues uptake of LDL occurs primarily in the liver through LDL-receptor-mediated endocytosis, which requires the presence of apo-B-100. HDLs are synthesised essentially devoid of cholesterol or triacylglycerol and provide a circulating source of apo-C-I, II and apo-E. HDLs gradually accumulate cholesteryl esters, eventually returning these to the liver, mediated by an apo-A-I receptor this is referred to as reverse cholesterol transport. ...

Defect in lysosomal cholesteryl ester hydrolase affects metabolism of LDLs... 

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