VLDLs maturation

There is emerging evidence that VLDL assembly in general and MTP function in particular are intimately tied to assembly of hepatitis C virus (HCV) infectious particles [63]. MTP inhibition and ApoB downregula-tion in turn inhibit HCV assembly and maturation [64]. This may open new therapeutic opportunities for small-molecule MTP inhibitors in the... 

The fourth major lipoprotein type, high-density lipoprotein (HDL), originates in the liver and small intestine as small, protein-rich particles that contain relatively little cholesterol and no cholesteryl esters (Fig. 21-40). HDLs contain apoA-I, apoC-I, apoC-II, and other apolipoproteins (Table 21-3), as well as the enzyme lecithin-cholesterol acyl transferase (LCAT), which catalyzes the formation of cholesteryl esters from lecithin (phosphatidylcholine) and cholesterol (Fig. 21-41). LCAT on the surface of nascent (newly forming) HDL particles converts the cholesterol and phosphatidylcholine of chylomicron and VLDL remnants to cholesteryl esters, which begin to form a core, transforming the disk-shaped nascent HDL to a mature, spherical HDL particle. This cholesterol-rich lipoprotein then returns to the liver, where the cholesterol is unloaded some of this cholesterol is converted to bile salts. 

In adipose tissue, TAG is stored in the cytosol of the cells in a nearly anhydrous form. It serves as "depot fat," ready for mobilization when the body requires it for fuel. Little TAG is stored in the liver. Instead, most is exported, packaged with cholesteryl esters, cholesterol, phospholipid, and protein (apolipoprotein B-100, see p. 229) to form lipoprotein particles called very low density lipoproteins (VLDL). Nascent VLDL are secreted into the blood where they mature and function to deliver the endogenously-derived lipids to the peripheral tissues. [Note Recall that chylomicrons deliver primarily dietary (exogenously-derived) lipids.] Plasma lipoproteins are discussed in Chapter 18, p. 225. 

VLDL containing apoB-100, apoE, and apoC is secreted by the liver into the space of Disse. Metabolism of this triglyceride-rich particle by lipoprotein lipase leads to shrinkage of the core triglyceride component. As Eisen-berg and others have shown experimentally (E4), other VLDL components must be removed before the mature LDL particle is formed. These changes include removal of about 75% of the phospholipid, 85% of the unesterified cholesterol, and most of the apoC and apoE from the VLDL surface (E3). The mass of apoB per particle stays constant during metabolism of VLDL to LDL, but all other surface and core materials are diminished. 

Lipoproteins are assembled in two organs, the small intestine and the liver. The lipoproteins assembled in the intestine contain the lipids assimilated from the diet. These lipoproteins, called chylomicrons, leave the enterocyte and enter the bloodstream via the Lymphatic system. The lipoproteins assembled in the liver contain lipids originating from the bloodstream and from de novo synthesis in the liver. The term de novo simply means "newly made from simple components" as opposed to "acquired from the diet" or "recycled from preexisting complex components." These lipoproteins, called very-low-dcnslty lipoproteins (VLDLs), are secreted from the liver into the bloodstream. The liver also synthesizes and secretes other Lipoproteins called high-density Lipoproteins (HDLs), which interact with the chylomicrons and VLDLs in the bloodstream and promote their maturation and function. The data in Table 6-4 show that chylomicrons contain a small proportion of protein, whereas HDLs have a relatively high protein content. Of greater interest is the identity and function of the proteins that constitute these particles. These proteins confer specific properties to lipoprotein particles, as detailed later in this chapter. 

An alternative metabolic pathway is available to a VLDL. in this process, the particle loses its apo E as it matures to an IDL. Without apo E, the particle is not efficiently taken up by the liver but continues to circulate in the bkKdstream. Continued removal of TGs from an IDL produces a lipoprotein particle called an LDL that is enriched in cholesteryl esters. After conversion to an LDL, only a single apo B molecule remains on the surface of the particle. This protein binds only relatively weakly to an LDL receptor. Consequently, LDLs have residence times in the circulation of about 3 days. Eventually, LDLs are taken up by various tissues. The receptor that binds an LDL, called an LDL receptor, is similar, or perhaps identical, to the receptors that bind circulating IDLs and mediate their entry into hepatocytes. 

F[GURE 6,17 i athwAyB uf maturation of the chyloinicrons and VLDLs and of release of the fatty acids from these particles. 

Several of the concepts described in this section are illustrated on the lipoprotein map (Figures 6.IB and 6,19). The map depicts the synthesis of chylomicrons in the gut and their Flow up the thoracic duct to the circulation. The figure also shows the release of fatty acids frtjm these particles in various tissues and the uptake of the remnants by the hepatocytes of the liver. A similar fate Is shown for the VLDLs synthesized in the liver. As shown, they mature to LDIs, w hich deliver cholesterol to various tissues. 

HDLs are secreted in nascent form by hepatocytes and en-terocytes (Figure 20-7). Loss of surface components, including phospholipids, free cholesterol, and protein from chylomicrons and VLDL as they are acted on by lipoprotein lipase, may also contribute to formation of HDL in plasma. Discoidal, nascent HDL is converted to spherical, mature HDL by acquiring free cholesterol from cell membranes or other lipoproteins. This function of HDL in peripheral cholesterol removal may underlie the strong inverse relationship between plasma HDL levels and incidence of coronary heart disease. After esterification of HDL surface cholesterol by LCAT, which is activated by apo A-I, HDL sequesters the cholesteryl ester in its hydrophobic core. This action increases the gradient of free cholesterol between the cellular plasma membrane and HDL particles. Cholesteryl esters are also transferred from HDL to VLDL and LDL via apo D, the cholesteryl ester transfer protein (Figure 20-8). 

As far as HDL levels and metabolism are concerned, one result of the LCAT- and transfer protein-catalyzed reactions is the production of a dynamic spectrum of particles with a wide range of sizes and lipid compositions (Chapter 19). Nascent HDL particles contain mostly apo A1 and phospholipids, and undergo modulation and maturation in the circulation. For instance, the unesterified cholesterol incorporated into plasma HDL is converted to cholesteryl esters by LCAT, creating a concentration gradient of cholesterol between HDL and cell membranes, which is required for efficient cholesterol efflux from cells to HDL. In addition, cholesteryl ester transfer protein transfers a significant amount of HDL cholesteryl ester to VLDL, IDL, and LDL for further transport, primarily to the liver. Thus, a substantial fraction of cell-derived cholesterol is delivered as part of HDL indirectly to the liver via hepatic endocytic receptors for IDL and LDL this process is termed reverse cholesterol transport . However, receptor-mediated delivery of HDL cholesterol to cells is fundamentally different from the classic LDL receptor-mediated endocytic pathway, as described in Section 7.3.2. 

The principal function of high density lipoprotein (HDL) is to transport excess cholesterol obtained from peripheral tissues to the liver and to exchange proteins and lipids with chylomicrons and VLDL. The protein exchange converts nascent particles to mature particles. 

VLDL is processed in the Golgi complex and secreted into the blood by the liver (Figs. 33.22 and 33.23). The fatty acid residues of the triacylglycerols ultimately are stored in the triacylglycerols of adipose cells. Note that, in comparison to chylomicrons (see Chapter 32), VLDL particles are more dense, as they contain a lower percentage of triglyceride than do the chylomicrons. Similar to chylomicrons, VLDL particles are first synthesized in a nascent form, and on entering the circulation they acquire apoproteins CII and E from HDL particles to become mature VLDL particles. 

LPL is the major enzyme responsible for the hydrolysis of circulating TAG moiety of both classes of TAG-rich lipoproteins the chylomicrons and VLDL, generating FFA, that are either oxidized in the muscles or reesterified in the adipose tissues, and glycerol that is returned to the liver. LPL plays a central role in overall lipoprotein metabolism, where (1) the successive interaction of VLDL with LPL generates the LDL that are involved in forward cholesterol transport and (2) the remnant lipoprotein particles so formed from LPL catalysis contributes to the maturation of HDL precursors, the latter of which is then involved in reverse cholesterol transport [21, 22], Perturbation in LPL activity could therefore lead to significant metabolic consequences, and LPL has been implicated in pathophysiological conditions characterized... 

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