Chylomicrons lipolysis

LRP is a member of the LDL receptor gene family (ref. 649) and, like the LDL receptor, performs an essential role in the removal of certain lipoprotein particles from the bloodstream. As Heeren et al. (ref. 650) explain, triglycerides are transported mainly by two distinct classes of lipoproteins, the chylomicrons and the very-low-density lipoproteins (VLDL). After assembly in the intestine, chylomicrons are carried via lymph into the bloodstream, where they are transformed at the endothelial surface to remnant lipoproteins through the catalytic action of lipoprotein lipase (for review, see ref. 651,652). After lipolysis, the lipoprotein lipase remains associated with the chylomicron remnants and, in conjunction with apolipoprotein E (apo E) (ref. 653-655), facilitates their clearance by the liver into hepatocytes (ref. 656) via LDL receptors and the LRP (ref. 657-660). (The essential role for both receptors in chylomicron remnant removal in vivo has been demonstrated in gene knockout and gene transfer experiments (ref. 661,662 for review, see ref. 663).)... 

The chylomicron remnant particles themselves, derived from lipolysis of the larger chylomicrons (cf. above), contain the residual triglyceride and all of the cholesterol and cholesterol ester from the original chylomicrons. This lipid composition of the chylomicron remnant particles is similar to the above-described lipid composition of both LDL particles (cf. Section 14.1) and LCM (cf. Section 12.1). Based upon this molecular similarity, it appears reasonable to expect that injected LCM could also readily bind apo E (i.e., as an alternative to apo B) in the bloodstream. In this case, the proposed LCM binding of apo E should influence the subsequent biodistribution of those LCM via two endocytic pathways specifically, one pathway mediated by the LDL receptor (a.k.a. apo B,E receptor ) (cf. Section 14.1) and the other pathway mediated by the LRP, since both receptor types have a high affinity for apo E (cf. above). 

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. 

FAs in plasma - the so-called free fatty acids (FFA) although they are bound to albumin [74] - stem mainly from lipolysis inside the adipocytes and spill-over from the LPL lipolysis [98]. FFA can be taken up and oxidized by most cells, particularly muscle cells [74]. For example the heart lives mainly on fat oxidation [62, 74]. Also the liver takes up FFAs. Some is oxidized, but a large fraction is rebuilt to TG and released to blood as very low density lipoproteins (VLDLs) [74]. The VLDLs undergo the same fate as chylomicrons, but their lipolysis rate is lower. 

There is good evidence that nascent chylomicrons acquire apoC and apoE from HDL present in lymph and blood plasma (G28, 14). The fete of apoE during the hydrolysis of chylomicron triglyceride by lipoprotein lipase is unknown. Perhaps some apoE is lost to the HDL fraction during lipolysis, in the same way that redundant phospholipid and apoC are lost (H17, M38). 

Vitamin E, like neutral lipids, requires apoB lipoproteins at every stage of its transport (Fig. 27-2). Dietary vitamin E becomes emulsified in micelles produced during the digestive phase of lipid absorption and permeates the intestinal epithelium, similar to fatty acids and cholesterol. Uptake of vitamin E by enterocytes appears to be concentration dependent. Within intestinal cells, vitamin E is packaged into chylomicrons and secreted into lymph. During blood circulation of chylomicrons, some vitamin E may be released to the tissues as a consequence of partial lipolysis of these particles by endothelial cell-anchored lipoprotein lipase. The rest remains associated with chylomicron remnants. Remnant particles are mainly endocy-tosed by the liver and degraded, resulting in the release of fat-soluble vitamins. 

Figure 1. Proposed yet speculative mechanism by which high-density lipoprotein (HDL) increases in response to exercise via increased lipoprotein lipase (LPL) activity. During lipolysis. components of Tg-rich lipoproteins are transferred to and incorporated into HDL, leading to the formation of HDL.. Very low density lipoprotein (VLDL), chylomicron (chylo).

Dietary retinyl esters are also processed in mucosal cells of the intestine through sequential de-esterification/re-esterification reactions (14). Retinyl esters are then incorporated into chylomicrons and pass from the intestine into the lymph fluid where lipolysis occurs, resulting in the formation of chylomicron remnants that continue to harbor retinyl esters. Chylomicron remnants containing retinyl esters en-... 

Normally more than 95% of ingested lipid is absorbed. When a large fraction is excreted in the feces, it is called steatorrhea. Measurement of fecal lipid with adequate lipid intake is a sensitive indicator of lipid malabsorption. Malabsorption can result from impairment in lipolysis (Table 12-6), micelle formation (Table 12-7), absorption, chylomicron formation, or transport of chylomicrons via the lymph to blood. 

Consequently, the apo B particle gradually becomes smaller, and denser. Functionally, very low-density lipoproteins (VLDLs, density <1.006 g/ml), intermediate density lipoproteins (IDLs, density 1.006-1.019 g/ml), and low-density lipoproteins (LDLs, density 1.019-1.063) represent a continuum created by the lipolysis of TG. Some IDL and all of LDL are cleared from the circulation by the liver. Residual lipids may be recycled in the form of new VLDL particles, or be catabolized and secreted into bile. While there are differences in the metabolism in the plasma of chylomicrons from the intestine, and VLDL from the liver, the same lipases are involved in both cases. 

A chylomicron or VLDL whose composition is optimized for lipolysis by LPL contains 10-20 molecules of apo C2/molecule of apo B. Titration of apo C2 levels against the rate of lipolysis has shown that no more than two or three apo C2 molecules per particle are needed for maximal TG hydrolysis rates. As lipolysis begins, and the surface area of the VLDL or chylomicron decreases, apo C proteins are displaced. This feature was probably developed to ensure that constant lipolysis rates of TG-rich lipoproteins are maintained until only small amounts of substrate remain, along with its apo B, apo E, and a few apo C proteins. The end-products of chylomicron and VLDL lipolysis ( remnants ) are removed by the liver via LDL receptors and other receptors (Chapter 20). 

Given the very large size of LPL substrate lipoproteins (chylomicrons and VLDLs) and the complex series of events involved in their remodeling in the course of lipolysis, it is... 

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.

Since lipid transfer proteins were demonstrated, it will be essential to demonstrate the common route of Apo C and phospholipids (with a specificity for each Apo C), when VLDL undergo lipolysis. The mechanism of Apo C transfer from HDL to triglyceride-rich lipoproteins (VLDL or chylomicrons) remains obscure. 

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