Chylomicrons roles

Dietary fats are required for carotenoid uptake by intestinal cells. Fats have an important role in the continuation of the process of carotenoid absorption, because the human intestine is incapable of secreting significant quantities of chylomicrons into the bloodstream in the absence of fats (Ornelas-Paz and others 2008b). Some studies have suggested that at least 5 g/day of dietary fat are required for suitable (3-carotene absorption (West and Castenmiller 1998), whereas others suggested the consumption... 

The best-known effect of APOE is the regulation of lipid metabolism (see Fig. 10.13). APOE is a constituent of TG-rich chylomicrons, VLDL particles and their remnants, and a subclass of HDL. In addition to its role in the transport of cholesterol and the metabolism of lipoprotein particles, APOE can be involved in many other physiological and pathological processes, including immunoregu-lation, nerve regeneration, activation of lipolytic enzymes (hepatic lipase, lipoprotein lipase, lecithin cholesterol acyltransferase), ligand for several cell receptors, neuronal homeostasis, and tissue repair (488,490). APOE is essential... 

Figure 7.23 Fate of blood triacylglycerol (in the chylomicrons and VLDL) in three conditions role of changes in activity of lipoprotein lipase in directing the uptake of fatty acids. It is primarily the activity of Lipoprotein lipase that directs which tissue/organ takes up the fatty acids from the blood triacylglycerol. The abbreviation LPLT indicates a change to a higher activity of lipoprotein lipase LPL-i indicates a change to a lower activity of lipoprotein lipase. The broadness of the arrow indicates the dominant direction of the fate of the fatty acid.

In chylomicron retention disease (Anderson s disease) the secretory defect is restricted to intestinal apoB-containing lipoproteins (i.e., chylomicrons). This very rare recessively inherited disorder results from defects in a GTPase, Sarlb, which plays a critical role in the intracellular assembly and trafficking of chylomicrons. The affected patients present with fat malabsorption resulting in steatorrhea and deficiency of fat-soluble vitamins [46, 52, 54]. 

The LDL receptor also binds to apoE and plays a significant role in the hepatic uptake of chylomicrons and VLDL remnants. However, if LDL receptors are unavailable (as, for example, in a mouse strain that lacks the gene for the LDL receptor), VLDL remnants and chylomicrons are still taken up by the liver even though LDL is not. This indicates the presence of a back-up system for receptor-mediated endocytosis of VLDL remnants and chylomicrons. One back-up receptor is lipoprotein receptor-related protein (LRP), which binds to apoE as well as to a number of other ligands. 

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 remarkable rapidity and specificity of uptake of the chylomicron remnant particles is believed to be highly dependent on their acquisition of apo E in the bloodstream (ref. 664,665) the critical role played by apo E in directing the clearance of chylomicron remnants from the (blood) plasma has been well... 

In Chapter 14, it was explained that the lipid composition of LCM (cf. Section 12.1) is similar to the lipid composition of both chylomicron remnant particles (cf. Section 14.2.1) and LDL particles (cf. Section 14.1). Based upon this molecular similarity, it was proposed that i.v. injected LCM could readily bind (as do chylomicron remnants) to apolipoprotein E in the bloodstream (cf. Section 14.2.1). Both the LDL receptor (a.k.a. apo B,E receptor ) and the LRP (cf. Section 14.2.1) have a high affinity for apo E (ref. 666), and both receptors play an essential role in the receptor-mediated endocytosis of chylomicron remnants (ref. 650,665,709). Accordingly, these two endocytic pathways have been proposed (together with scavenger receptor-mediated endocytosis) to influence LCM distribution in vivo in certain pathological states (cf. above). 

A. Rohlmann, M. Gotthardt, R.E. Hammer and J. Herz, Inducible inactivation of hepatic LRP gene by Cre-mediated recombination confirms role of LRP in clearance of chylomicron remnants, J. Clin. Invest. 101 (1998) 689-695. 

A major pathway by which LDL are catabolized in hepatocytes and other cells involves receptor-mediated endocytosis. Cholesteryl esters from the LDL core are hydrolyzed, yielding free cholesterol for the synthesis of cell membranes. Cells also obtain cholesterol by de novo synthesis via a pathway involving the formation of mevalonic acid by HMG-CoA reductase. Production of this enzyme and of LDL receptors is transcriptionally regulated by the content of cholesterol in the cell. Normally, about 70% of LDL is removed from plasma by hepatocytes. Even more cholesterol is delivered to the liver via remnants of VLDL and chylomicrons. Thus, the liver plays a major role in the cholesterol economy. Unlike other cells, hepatocytes are capable of eliminating cholesterol by secretion of cholesterol in bile and by conversion of cholesterol to bile acids. 

Lipoprotein lipase (EC 3.1.1.34) is an enzyme or group of enzymes which catalyze the hydrolysis of the 1(3) ester bond(s) of triacylglycerols and the 1 ester bond of phospholipids. The enzyme plays a central role in lipoprotein metabolism, being responsible in particular for the hydrolysis of chylomicron and VLDL triglycerides and the formation of remnant particles from these lipoproteins. There have been reviews of this enzyme [e.g., (N9, Ql)] and lipoprotein lipase will not be discussed in detail in this review. Familial lipoprotein lipase deficiency and related disorders of chylomicron metabolism have also been reviewed (B58, N8) and will not be discussed in detail. 

Ostlund-Lindqvist, A.-M., Gustafson, S., Lindqvist, P., Witztum, J. L., and Little, J. A., Uptake and degradation of human chylomicrons by macrophages in culture. Role of lipoprotein lipase. Arteriosclerosis 3, 433-440 (1983). 

Hussain MM, Kancha RK, Zhou Z, et al. Chylomicron assembly and catabolism role of apolipoproteins and receptors.Biochim BiophysActa 1300 151-170,1996. 

These lipids are insoluble in water and are classified on the basis of their ultracentrifugal properties into chylomicrons, very low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), low-density lipoprotein (LDL) and high-density lipoprotein (HDL) in order of ascending density. Table 2.4 gives the classification and roles of lipoproteins. 

Cholesterol and triacylglycerols are transported in body fluids in the form of lipoprotein particles. Each particle consists of a core of hydrophobic lipids surrounded by a shell of more polar lipids and apoproteins. The protein components of these macromolecular aggregates have two roles they solubilize hydrophobic lipids and contain cell-targeting signals. Lipoprotein particles are classified according to increasing density (Table 26.1) chylomicrons, chylomicron remnants, very low density lipoproteins (VLDL), intermediate-density lipoproteins (IDL), low-density lipoproteins (LDL), and high-density lipoproteins (HDL). Ten principal apoproteins have been isolated and characterized. They are synthesized and secreted by the liver and the intestine. 

Vitamin E plays an important role in cell metabolism as an antioxidant for the elimination of reactive oxygen intermediates. Subsequent to intestinal resorption, vitamin E is transported in chylomicrons into the liver, from where it reaches other organs together with VLDL. Vitamin E deficiency is observed in chronic liver diseases caused by alcohol, Wilson s disease, haemochromatosis and abetalipoproteinaemia. In vitamin E deficiency, neurologic disturbances (areflexia, dysbasia, ocular palsy, reduced perception of vibration) occur haemolysis can likewise be induced or become more pronounced due to epoxide formation of unsaturated fatty acids within the erythrocyte membranes. 

Although its role in lipoprotein metabolism has not been delineated fully, recent studies clearly imply that LRP is responsible for the clearance of a significant percentage of chylomicron remnants (Hussain et al., 1991 Mahley and Hussain, 1991). The interaction of apoE with the LRP has been most extensively studied using rabbit jS-VLDLs (Kowal et al., 1989, 1990). These cholesterol-enriched lipoproteins represent chylomicron remnants derived from the intestine and VLDL remnants from the liver. They contain multiple apoE molecules in addition to apoB and the low molecular weight apoC molecules. Interestingly, for rabbit )8-VLDLs to interact effectively with the LRP receptor, the apoE content of these lipoproteins must be first enriched by incuba-... 

Fig. 7. Role of hepatic lipoprotein receptors in lipoprotein metabolism. The central role of hepatic receptors and the importance of apoE in the clearance of chylomicron remnants (remnant receptor), VLDL (LDL receptors), IDL (LDL receptors), and HDL-with apoE (LDL receptors) are indicated. In addition, the suggested role of apoE and hepatic lipase (HL) in the conversion of IDL to LDL is shown.

Kane (1989)]. Chylomicron remnants are rapidly removed from plasma in a process known to be mediated by apoE (Shelburne et ai, 1980 Sherrill et al, 1980 Windier et al, 1980). The full details of this uptake process have not been completely defined. It has been postulated that the LRP receptor functions as the so-called remnant receptor (Kowal et al, 1989, 1990). In vivo evidence indicates that LRP is involved in uptake of chylomicron remnants (Hussain et al, 1991 Mahley and Hussain, 1991). In addition, LDL receptors also appear to play a role in uptake (Choi et al, 1991). Thus, at this point it appears that remnants may be cleared by two receptor systems. Therefore, in this regard, the scheme depicted in Fig. 7 is oversimplified. However, what clearly has been established is that apoE is a critical component of the chylomicron clearance process regardless of the receptor or receptors that are involved. 

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