Chylomicrons transfer protein

Cholesterol ester transfer protein catalyses the transfer of triacylglycerol from VLDL or chylomicrons to LDL and to HDL. However, it is the removal of this triacylglycerol from LDL and HDL, which occurs in the liver, via hepatic lipase, that causes problems small and dense LDL particles, which are more atherogenic than normal... 

The cholesteryl esters are transferred to VLDL, IDL, LDL, and chylomicron remnants with the aid of cholesteryl ester transfer protein (CETP). Much of the cholesteryl ester thus transferred is ultimately delivered to the liver by endocytosis of the acceptor lipoproteins. HDL can also deliver cholesteryl esters directly to the liver via a docking receptor (scavenger receptor, SR-BI) that does not cause endocytosis of the lipoproteins. 

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...

Assembly of chylomicrons The enzymes involved in triacylglycerol, cholesterol, and phospholipid synthesis are located in Ihe smooth ER. Assembly of the apolipoproteins and lipid into chylomicrons requires microsomal triacylglycerol transfer protein (see p. 229), which loads apo B-48 with lipid. This occurs during transition from the ER to the Golgi, where the particles are packaged in secretory vesicles. These fuse with the plasma membrane releasing the lipoproteins, which then enter the lymphatic system and, ultimately, the blood. 

Release of VLDLs VLDLs are secreted directly into the blood by the liver as nascent VLDL particles containing apolipoprotein B-100. They must obtain apo C-ll and apo E from circulating HDL (see Figure 18.17). As with chylomicrons, apo C-ll is required for activation of lipoprotein lipase. [Note Abetalipoproteinemia is a rare hypolipoproteinemia caused by a defect in triacylglycerol transfer protein, leading to an inability to load apo B with lipid. As a consequence, no chylomicrons or VLDLs are formed, and tria-cylglycerols accumulate in the liver and intestine.]... 

As the lipoproteins are depleted of triacylglycerol, the particles become smaller. Some of the surface molecules (apoproteins, phospholipids) are transferred to HDL. In the rat, remnants that result from chylomicron catabolism are removed by the liver. The uptake of remnant VLDL also occurs, but much of the triacylglycerol is further degraded by lipoprotein lipase to give the intermediate-density lipoprotein (IDL). This particle is converted into LDL via the action of lipoprotein lipase and enriched in cholesteryl ester via transfer from HDL by the cholesteryl ester transfer protein. The half-life for clearance of chylomicrons from plasma of humans is 4-5 min. Patients with the inherited disease, lipoprotein lipase deficiency, clear chylomicrons from the plasma very slowly. When on a normal diet, the blood from these patients looks like tomato soup. A very-low-fat diet greatly relieves this problem. 

The apoproteins of HDL are secreted by the liver and intestine. Much of the lipid comes from the surface monolayers of chylomicrons and VLDL during lipolysis. HDL also acquire cholesterol from peripheral tissues in a pathway that protects the cholesterol homeostasis of cells. In this process, free cholesterol is transported from the cell membrane by a transporter protein, ABCA1, acquired by a small particle termed prebeta-1 HDL, and then esterified by lecithin cholesterol acyltransferase (LCAT), leading to the formation of larger HDL species. The cholesteryl esters are transferred to VLDL, IDL, LDL, and chylomicron remnants with the aid of cholesteryl ester transfer protein (CETP). Much of the cholesteryl ester thus transferred is ultimately delivered to the liver by endocytosis of the acceptor lipoproteins. HDL can also deliver cholesteryl esters directly to the liver via a docking receptor (scavenger receptor, SR-BI) that does not endocytose the lipoproteins. 

Cholesterol esters may be transferred to IDL, chylomicron remnants, and to LDL via a transfer protein (ApoD) or nonspecifically. In addition, HDL carrying the... 

In intestinal mucosal cells, all vitamers of vitamin E cue incorporated into chylomicrons, and tissues take up some vitamin E from chylomicrons. Most, however, goes to the liver in chylomicron remnants, a -Tocopherol, which binds to the liver a-tocopherol transfer protein, is then exported in very low-density lipoprotein (VLDL) and is available for tissue uptake (Traber and Aral, 1999 Stocker and Azzi, 2000). Later, it appears in low-density Upoprotein (LDL) and high-density lipoprotein, as a result of metabolism of VLDL in the circulation. The other vitamers, which do not bind well to the a-tocopherol transfer protein, are not incorporated into VLDL, but are metabolized in the Uver and excreted. This explains thelower biological potency of the othervitcimers,despitesimilar, or higher, in vitro antioxidant activity. 

In this autosomal recessive disease, the disorder does not involve the gene on chromosome 2, which is responsible for apoprotein assembly, but the MTP gene (microsomal triglyceride transfer protein), which is localized on chromosome 4 q 22—24. In the endoplasmic reticulum, MTP transfers cholesterol esters, triglycerides and phospholipids to the nascent apoprotein B. This process is a prerequisite for the transport of the complete lipoproteins (e.g. chylomicrons, VLDL) to the Golgi complex and their secretion into the blood via subsequent exocytosis. In the case of MTP deficiency, lipoprotein particles are not secreted, with the result that any superfluous apoprotein B is broken down in the endoplasmic reticulum. (214, 216, 219, 220)... 

The various forms of vitamin E are all absorbed by the gut in proportion to their abundance in the diet, where they appear in the chylomicrons. As the chylomi-cn>ns travel through the blood, the various forms of vitamin E are partly transferred to all the other types of lipoprotein particles. However, once vitamin E enters the liver, ct-tcKopherol is the only form that is preferentially packaged into the V ,DLs Traber, 1997). This preference seems to be a result of the activity of oc-tocopheiol transfer protein. This is a small protein that exists only in the cytoplasm of hepalocytcs,... 

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). 

Only two types of lipoproteins, VLDL and chylomicrons, are fully formed within cells by assembly in the ER, a process that requires the activity of microsomal transfer protein. The assembled particles move through the secretory pathway to the cell surface and are released by exocytosis—VLDL from liver cells and chylomicrons from intestinal epithelial cells (see Figure 18-10b). LDLs, IDLs (intermediate-density lipoproteins), and some HDLs are generated extracellularly in the bloodstream and on the surfaces of cells by the remodeling of secreted VLDLs and chylomicrons. There are four types of modifications ... 

Though chylomicrons and VLDLs are both substrates for LPL, the processing of the end-products of their metabolism is quite different. Chylomicron remnants recirculate until about 80% of their original TG content has been removed. These remnants retain almost the whole of their content of CE and retinyl ester. Excess surface molecules (mainly apo C proteins, cholesterol, and phospholipids) are transferred from the remnants, either spontaneously or by the activity of phospholipid transfer protein, mainly to HDLs. The chylomicron remnants, with apo E as the major ligand, are cleared quantitatively by hepatic receptors of the LDL receptor family. 

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.

Without the enzyme microsomal triglyceride transfer protein (MTP), hepatic triglycerides cannot be transferred to apoB-100. Patients with dysfunctional MTP fail to make any of the apoB-containing lipoproteins (VLDL, IDL, or LDL). MTP also plays a key role in the synthesis of chylomicrons in the intestine, and mutations of MTP that result in the inability of triglycerides to he transferred to either apoB-100 in the liver or apoB-48 in the intestine prevent VLDL and chylomicron production and cause the genetic disorder abetalipoproteinemia. 

Abetalipoproteinemia, which is due to a lack of MTP (microsomal triglyceride transfer protein see Chapter 32) activity, results in an inability to assemble both chylomicrons in the intestine and VLDL particles in the liver. 

Fig. 34.16. Functions and fate of FiDL. Nascent FiDL is synthesized in liver and intestinal cells. It exchanges proteins with chylomicrons and VLDL. HDL picks up cholesterol (C) from cell membranes. This cholesterol is converted to cholesterol ester (CE) by the LCAT reaction. HDL transfers CE to VLDL in exchange for triacylglycerol (TG). The cholesterol ester transfer protein (CETP) mediates this exchange. PL = phospholipids.

Together with dietary fat, both tocopherols and tocotrienols are absorbed in the digestive tract, incorporated into chylomicrons, and transported in the lymphatic system. However, following chylomicron clearance, tocotrienols disappear from circulating plasma, whereas tocopherol, especially a-tocopherol, is preferentially secreted into plasma. a-Tocopherol transfer protein, which controls plasma a-tocopherol levels, has an affinity of only 12% for a-tocotrienol (compared with 100% for a-tocopherol). The reason for the low plasma tocotrienol concentrations compared with tocopherols is the very fast clearance, as demonstrated by Yap et al. ... 

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