Chylomicrons cholesterol transport

HDL concentrations vary reciprocally with plasma triacylglycerol concentrations and directly with the activity of lipoprotein lipase. This may be due to surplus surface constituents, eg, phospholipid and apo A-I being released during hydrolysis of chylomicrons and VLDL and contributing toward the formation of preP-HDL and discoidal HDL. HDLj concentrations are inversely related to the incidence of coronary atherosclerosis, possibly because they reflect the efficiency of reverse cholesterol transport. HDL, (HDLj) is found in... 

Four major groups of lipoproteins are recognized Chylomicrons transport lipids resulting from digestion and absorption. Very low density lipoproteins (VLDL) transport triacylglycerol from the liver. Low-density lipoproteins (LDL) deliver cholesterol to the tissues, and high-density lipoproteins (HDL) remove cholesterol from the tissues in the process known as reverse cholesterol transport. 

Apo B is structural apolipoprotein for chylomicrons and for VLDL and LDL particles. It is synthesized in enteric and hepatic cells. It is important for cholesterol transport to cells via interaction with LDL receptors. 

Apolipoprotein B. Apo B is a structural apolipoprotein for chylomicrons, VLDL, and LDL particles. It is synthesized in enteric and hepatic cells. It is important for cholesterol transport to cells via interaction with LDL receptors. Nowadays, it seems its clinical relevance in CSF investigation is near Apo A-I and Apo A-II, but in current studies some varieties can be found (A23, T3). 

The HDL lipids are removed from the circulation by a selective uptake and by an indirect pathway. The selective uptake of cholesterol esters from HDL into he-patocytes and steroidogenic cells is mediated by the binding of HDL to scavenger receptor B1 (SR-BI). This selective uptake by SR-BI may depend on the presence of cofactors such as HL, which hydrolyses phospholipids on the surface of both HDL and plasma membranes and thereby enables the flux of cholesteryl esters from the lipoprotein core into the plasma membrane [42]. The indirect pathway involves the enzyme CETP, which exchanges cholesteryl esters of a-HDL with triglycerides of chylomicrons, VLDL, IDL, and LDL. The a-HDL derived cholesteryl esters are therefore removed via the LDL-receptor pathway. The removal of excess cholesterol from the periphery and the delivery to the liver for excretion in the bile is termed reverse cholesterol transport. 

HDL may be taken up in the liver by receptor-mediated endocytosis, but at least some of the cholesterol in HDL is delivered to other tissues by a novel mechanism. HDL can bind to plasma membrane receptor proteins called SR-BI in hepatic and steroidogenic tissues such as the adrenal gland. These receptors mediate not endocytosis but a partial and selective transfer of cholesterol and other lipids in HDL into the cell. Depleted HDL then dissociates to recirculate in the bloodstream and extract more lipids from chylomicron and VLDL remnants. Depleted HDL can also pick up cholesterol stored in extrahepatic tissues and carry it to the liver, in reverse cholesterol transport pathways (Fig. 21-40). In one reverse transport path, interaction of nascent HDL with SR-BI receptors in cholesterol-rich cells triggers passive movement of cholesterol from the cell surface into HDL, which then carries it back to the liver. In a second pathway, apoA-I in depleted HDL in-... 

As mentioned in Chapter 21, there are several related receptors with similar structures. Two of them have a specificity for apolipoprotein E and can accept remnants of VLDL particles and chylomicrons.216 220 The LDL receptor-related protein is a longer-chain receptor.216 221 LDL particles, especially when present in excess or when they contain oxidized lipoproteins, may be taken up by endocytosis into macrophages with the aid of the quite different scavenger receptors.221 225 The uptake of oxidized lipoproteins by these receptors may be a major factor in promoting development of atherosclerosis (Box 22-B). On the other hand, scavenger receptor SR-B1, which is also present in liver cells, was recently identified as the receptor for HDL and essential to the "reverse cholesterol transport" that removes excess cholesterol for excretion in the bile.213/213a... 

FIG. 1 Movement of cholesterol (CHOL) and bile acids (BA) between the liver and small intestine. CHOL and BA in the liver are secreted into the gallbladder where they are stored temporarily until a fat-containing meal causes their secretion into the intestinal lumen. BA are absorbed with high efficiency (95%) and are recycled back to the liver via the hepatic portal vein. CHOL is absorbed less efficiently (50-60%) and must be incorporated into lipoproteins (chylomicrons) for transport back to the fiver via the systemic circulation. Accumulation of CHOL in the liver can promote secretion of CHOL into plasma, thus increasing LDL-CHOL concentration. Loss of CHOL and BA in feces represents the primary route of CHOL elimination from the body. 

Profiling of plasma lipoproteins and serum lipids can often aid in the diagnosis of Tangier disease. There are four classes of lipoproteins (1) chylomicrons, which transport dietary cholesterol and triglycerides from the intestines to the tissues (2) very low-density lipoproteins (VLDL) and (3) low-density lipoproteins (LDL), both of which transport de novo synthesized cholesterol and triglyceride from the liver to the tissues and (4) high-density lipoproteins (HDL), which mediate reverse cholesterol transport, a process in which excess cholesterol from peripheral tissues is transported to the liver. 

HDL, like LDL, is a cholesterol-rich particle, and is distinct from the other lipoprotein classes in that it does not contain apoB. HDL levels are inversely correlated with risk for atherosclerosis (Wilson et al., 1988). Nascent HDL particles are produced by direct synthesis (Hamilton, 1984), and excess surface remnants from chylomicrons and VLDL produced during the action of lipoprotein lipase (as noted above) enter the HDL density class. HDL appears to be involved in delivery of cholesterol to steroidogenic tissues as well as the removal of excess cholesterol from peripheral tissues and excretion from the system. This HDL-mediated removal of cholesterol has been termed reverse cholesterol transport (Glomset, 1968). Although apolipoproteins present in HDLs are cleared by the liver, the reverse cholesterol transport pathway has never been directly demonstrated. HDL can remove cholesterol from tissues, a process that may be partially mediated by interaction with a putative HDL receptor, with apoA-I as the ligand for that receptor (Oram el ai, 1983). The existence of an HDL receptor remains controversial saturable HDL binding may not be mediated by a specific apolipoprotein ligand and may not even be required for transfer of cholesterol from cells to... 

The laws of mass action govern the interactions of lipids and most apoproteins in lipoproteins, so that as the affinities between surface components change dining lipoprotein metabolism, apoproteins may dissociate from one particle and bind to another. In fact, all of the apoproteins, with the possible exception of apoprotein B (apo B), can change their lipoprotein associations. The reason for the unique behavior of apo B remains a mystery. On the basis of their principal transport function, lipoproteins may be divided into two classes according to the composition of their major core lipids. The principal triacylglycerol carriers are chylomicrons and very-low-density lipoproteins (VLDLs), whereas most cholesterol transport occurs via LDLs and HDLs. 

LPL converts chylomicrons to chylomicron remnants and VLDL to intermediate density lipoprotein (IDL). These products, which have a relatively low triacylglyc-erol content, are taken up by the liver by the process of endocytosis and degraded by lysosomal action. IDL may also be converted to low density lipoprotein (LDL) by further digestion of triacylglycerol. Endocytosis of LDL occurs in peripheral tissues as well as the liver (Table VI. 1), and is the major means of cholesterol transport and delivery to peripheral tissues. 

After entry in the blood stream the chylomicrons are hydrolyzed by the endothelial-bound lipoprotein lipase with apo C-I as a co-factor, allowing the delivery of free FAs to muscle and adipose tissue. The chylomicron remnants are rapidly taken up into the liver via especial receptor. ApoE is the moiety required for rapid hepatic removal. Its activity is inhibited by C apolipoproteins, especially apoC-I. The liver utilizes the exogenous fat and can release surplus lipids via VLDL into the blood. The VLDL is another substrate for lipoprotein lipase. The remaining VLDL remnants can either be taken up into the liver or are hydrolyzed to LDL. These last delivers cholesterol to all body cells via its receptor [136]. Moreover other type of lipoprotein denominated as high-density protein (HDL) is an important scavenger of surplus cholesterol transporting it from cell membranes to the liver, where it is degraded or converted into biliary salts, an then eliminated by the entero-hepatic cycle [137]. 

Function Transport dietary TAG and cholesterol from the intestines to the periphery Forward transport of endogenous TAG and cholesterol from liver to periphery Precursor of LDLs Cholesterol transport 1 Reverse transport of cholesterol from periphery to the liver 2 Stores apoprotein C2 and apoprotein E which it supplies to chylomicrons and VLDLs 3 Scavenges and recycles apolipoproteins released from chylomicrons and VLDL following lipoprotein lipase activity in the capillaries... 

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... 

Chylomicron remnants deliver dietary cholesterol to the liver. It is then incorporated into very low-density lipoproteins (VLDL), which are secreted in plasma. The VLDL acquire cholesteryl esters and apolipoprotein E (apo E) from high-density lipoproteins (HDL) to produce intermediate-density lipoproteins (IDL), which are rapidly taken up by the liver or are further catabolized into low-density lipoproteins (LDL). These cholesterol-rich LDL particles are catabolized only slowly in human plasma and are therefore present at relatively high concentrations. Elimination of cholesterol from these extra-hepatic cells is achieved by the delivery of cholesterol from cell membranes to plasma HDL in the first step of a pathway known as reverse cholesterol transport. This process allows for esterification of cholesterol and its delivery back to the liver. 

HDL and VLDL are assembled primarily in the endoplasmic reticulum of the liver (with smaller amounts produced in the intestine), whereas chylomicrons form in the intestine. LDL is not synthesized directly, but is made from VLDL. LDL appears to be the major circulatory complex for cholesterol and cholesterol esters. The primary task of chylomicrons is to transport triacylglycerols. Despite all this, it is extremely important to note that each of these lipoprotein classes contains some of each type of lipid. The relative amounts of HDL and LDL are important in the disposition of cholesterol in the body and in the development of arterial plaques (Figure 25.36). The structures of the various... 

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. 

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