HDL particles

PLTP is responsible for the majority of phospholipid transfer activity in human plasma. Specifically, it transfers surface phospholipids from VLDL to HDL upon lipolysis of triglycerides present in VLDL. The exact mechanism by which PLTP exerts its activity is yet unknown. The best indications for an important role in lipid metabolism have been gained from knockout experiments in mice, which show severe reduction of plasma levels of HDL-C and apoA-I. This is most likely the result of increased catabolism of HDL particles that are small in size as a result of phospholipid depletion. In addition to the maintenance of normal plasma HDL-C and apoA-I concentration, PLTP is also involved in a process called HDL conversion. Shortly summarized, this cascade of processes leads to fusion of HDL... 

Niacin (vitamin B3) has broad applications in the treatment of lipid disorders when used at higher doses than those used as a nutritional supplement. Niacin inhibits fatty acid release from adipose tissue and inhibits fatty acid and triglyceride production in liver cells. This results in an increased intracellular degradation of apolipoprotein B, and in turn, a reduction in the number of VLDL particles secreted (Fig. 9-4). The lower VLDL levels and the lower triglyceride content in these particles leads to an overall reduction in LDL cholesterol as well as a decrease in the number of small, dense LDL particles. Niacin also reduces the uptake of HDL-apolipoprotein A1 particles and increases uptake of cholesterol esters by the liver, thus improving the efficiency of reverse cholesterol transport between HDL particles and vascular tissue (Fig. 9-4). Niacin is indicated for patients with elevated triglycerides, low HDL cholesterol, and elevated LDL cholesterol.3... 

Although apoE HDL particles are formed by astrocytes in vitro, the brain contents of apoE knockout (-/-) were not found to differ in lipid content in comparison to those obtained from normal animals [14]. A probable explanation is that newly synthesized cholesterol can be transported from astrocyte ER to plasma membrane via an alternative route that employs caveolae to form apoAl-HDL [15]. 

ApoA-1 is the major structural lipoprotein component of HDL particles. Transgenic over-expression of apoA-1 has been well documented to correlate very strongly with antiatherogenic effects seen in a number of animal models [89-91]. The genetic deficiency of apoA-1 in humans has also been linked to low levels of HDL and premature atherosclerosis [90-92]. It is believed that infusion of apoA-1 enhances the ABCAl-mediated cholesterol efflux from macrophages [93]. During the last decade, significant efforts have been spent to find small... 

HDL particles will remove cholesterol from cells and the component enzyme LCAT esterifies cholesterol whilst it is part of the HDL... 

Chylomicroiis leave the lymph and enter the peripheral blood where the thoracic duct joins the left subdavian vein, thus initially bypassing the hver. After a high-fat meal, chylomicrons cause serum to become turbid or milky. While in the blood, chylomicrons acquire apoC-II and apoE from HDL particles. 

After triglyceride is removed from the VLDL, the resulting partide is referred to as either a VLDL remnant or as an IDL. A portion of the IDLs are picked up by hepatocytes through their apoE receptor, but some of the IDLs remain in the blood, where they are further metabolized. These IDLs are transition particles between triglyceride and cholesterol transport. In the blood, they can acquire cholesterol transferred from HDL particles and thus become converted into LDLs, as shown in Figure 1-15-6. 

HDL particles are able to transfer cholesterol from tissue cells to LDL particles. In this way, cholesterol is transported from tissues to the liver. 

In addition, triacylglycerols can be transferred to HDL particles transforming the VLDL into LDL. 

G. HDL particles have several functions, but among the most important is transport of excess cholesterol scavenged from the cell membranes back to the liver, a process called reverse cholesterol transport. 

HDL particles extract cholesterol from peripheral membranes and, after esterification of cholesterol to a fatty acid, the cholesteryl esters are delivered to the liver (to make bile salts) or steroidogenic tissues (precursor of steroids). 

In this way, HDL particles participate in disposal of cholesterol, and thus, a high HDL concentration is considered a protective factor against the development of cardiovascular disease. 

Apo A-I is the main structural apolipoprotein on HDL particles it is synthesized in hepatic and enteric cells. Bound phosphatidylcholine and sphingomyelin participate in the creation of protein-phospholipid complexes. 

The elevation of HDL levels by fibrates may be due to two drug actions induced synthesis of apo-Al, the principal apoprotein of HDL, and increased assembly of new HDL particles in the circulation. Sirrface components of VLDL contribute to formation of HDL, as the VLDL particles are reduced in size through the action of LPL. The increased rate of catabolism of VLDL caused by the fibrates would provide more components for assembly of HDL particles. 

In blood, lipids exist as lipoprotein particles, the main function of which is to transport lipids to and from various tissues and organs of the body. There is considerable interest in blood lipoproteins from the viewpoint of human health, especially obesity and cardiovascular diseases. Lipoproteins are classified into four groups on the basis of density, which is essentially a function of their triglyceride content, i.e. chylomicrons, very low density lipoprotein particles (VLDL), low density lipoprotein (LDL) particles and high density lipoprotein (HDL) particles, containing c. 98, 90, 77 and 45% total lipid, respectively (Figure 3.11). 

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. 

HDLs comprise a heterogeneous family of lipoproteins with a complex metabolism that is not yet completely understood. HDL particles are secreted directly into blood from the liver and intestine. HDLs perform a number of important functions, including the following ... 

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). 

HDL uptake of unesterified cholesterol Nascent HDL are diskshaped particles containing primarily phospholipid (largely phosphatidylcholine) and apolipoproteins A, C, and E. They are rapidly converted to spherical particles as they accumulate cholesterol (Figure 18.23). [Note HDL particles are excellent acceptors of unesterified cholesterol (both from other lipoproteins particles and from cell membranes) as a result of their high concentration of phospholipids, which are important solubilizers of cholesterol.]... 

While the primary role of LDL appears to be the transport of esterified cholesterol to tissues, the high density lipoproteins (HDL) carry excess cholesterol away from most tissues to the liver 205 207 The apoA-I present in the HDL particle not only binds lipid but activates LCAT, which catalyzes formation of cholesteryl esters which migrate into the interior of the HDL and are carried to the liver. 

Unlike other lipoproteins, HDL particles are assembled outside of cells from lipids and proteins, some of which may be donated from chylomicrons (see Fig. 21-1) or other lipoprotein particles. HDL has a higher protein content than other lipoproteins and is more heterogeneous. The major HDL protein is apolipoprotein A-I, but many HDL particles also contain A-jj 205,208-210 ancj apolipoproteins A-IV, D, and E may also be present. A low plasma level of HDL cholesterol is associated with a high risk of atherosclerosis.205 207... 

Unlike fatty acids, cholesterol is not degraded to yield energy. Instead excess cholesterol is removed from tissues by HDL for delivery to the liver from which it is excreted in the form of bile salts into the intestine. The transfer of cholesterol from extrahepatic tissues to the liver is called reverse cholesterol transport. When HDL is secreted into the plasma from the liver, it has a discoidal shape and is almost devoid of cholesteryl ester. These newly formed HDL particles are good acceptors for cholesterol in the plasma membranes of cells and are converted into spherical particles by the accumulation of cholesteryl ester. The cholesteryl ester is derived from a reaction between cholesterol and phosphatidylcholine on the surface of the HDL particle catalyzed by lecithimcholesterol acyltransferase (LCAT) (fig. 20.17). LCAT is associated with FIDL in plasma and is activated by apoprotein A-I, a component of HDL (see table 20.3). Associated with the LCAT-HDL complex is cholesteryl ester transfer protein, which catalyzes the transfer of cholesteryl esters from HDL to VLDL or LDL. In the steady state, cholesteryl esters that are synthesized by LCAT are transferred to LDL and VLDL and are catabolized as noted earlier. The HDL particles themselves turn over, but how they are degraded is not firmly established. 

There is also evidence from the rat that HDL particles, rich in apoA-I and containing little apoE, are secreted from the intestine into mesenteric lymph... 

There is immunochemical evidence that in man apoA-II is produced in intestinal epithelial cells (B33, S16, S20). Anderson et al. estimated that 28-82% of total body apoA-II synthesis takes place in the intestine (A23). Most lymph apoA-II (90 11%) is associated with HDL particles. As with apoA-I, a high proportion (perhaps more than 70%) of thoracic duct apoA-II is calculated to be derived originally from plasma and to be recirculating back into the plasma (A23). 

Parks and Rudel (P4) showed in African green vervet monkeys that the kinetic fete of apoA-II on lymph chylomicrons introduced into plasma differed from that of apoA-I. ApoA-I metabolism has been discussed (Sections 4.2 and 4.3). ApoA-II was transferred immediately from chylomicrons to HDL particles. It is possible that in so doing it may displace apoA-I from HDL (L2, R19) the data of Parks and Rudel are consistent with this possibility. 

The means whereby apoA-II is finally cleared from the circulation is unknown. Because the affinity of apoA-II for HDL particles appears to be greater than that of apoA-I, it is possible that apoA-II is cleared from the circulation only as part of an HDL particle. 

Evidence from rats suggests that apoE is synthesized almost exclusively in the liver (M31, W19). Perfusion experiments show that the liver produces discoid nascent HDL particles which are rich in apoE, and which also contain apoA-I (Dl, D2, F8, H3, H5, Kll, M31). ApoE is not found in chylomicrons of intestinal lymph, and its presence in chylomicrons in blood suggests that a transfer from nascent HDL to chylomicrons occurs (G28, 14). 

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