Clearance, chylomicron remnants

Familial dyslipo-proteinemia III IDL 0-VLDL) Chol,TG Decreased plasma clearance of VLDL and chylomicron remnants due to abnormal Apo E (E2 for normal E3). CHD, stroke... 

ApoE 34,145 Chylomicrons, VLDL, HDL Triggers clearance of VLDL and chylomicron remnants... 

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... 

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.D. Cooper, Hepatic clearance of plasma chylomicron remnants, Semin. Liver Dis. 12 (1992) 386-396. 

The WHHL model has stimulated major advances in our understanding of apoB receptors (G22). In particular, it has allowed a clear differentiation of two kinds of hepatic receptors one involved in the uptake of chylomicron remnants, recognizing (it is thought) apoE when in a particle containing apoB-48, and the other involved in the hepatic uptake of apoB-100-contain-ing VLDL, IDL, and LDL particles. The apoB-100 receptors, which also have an affinity for apoE and are referred to in this review as apoB-100, E receptors, are found in many extrahepatic cells. The WHHL rabbit is deficient in apoB-100, E receptors, but not in those receptors responsible for chylomicron clearance. 

ApoE-containing HDL, obtained by heparin-Sepharose affinity chromatography, contains apoA-I, apoA-II, and apoC, as well as apoE (W12, W18). Clearance frou. the plasm, appears to be dependent on a specific hepatic receptor for apoE, which binds apoE-containing HDL and chylomicron remnants, but not other lipoproteins (H35, Mil, S28). Canine apoE-HDLC, with apoE as the only detectable apoprotein, is cleared from the plasma very rapidly by the liver (more than 90% in the first 20 minutes after intravenous injection) (M15). In adult man, dogs, and swine the apoE receptor numbers do not seem to be significantly reduced by cholesterol feeding (H35, Mil). 

Sherrill, B, C., Innerarity, T. L., and Mahley, R. W., Rapid hepatic clearance of the canine lipoproteins containing only the E apoprotein by a high affinity receptor Identity with the chylomicron remnant transport process. /. Biol. Chetn. 255, 1804-1807 (1980). 

Chylomicron remnants and very low density lipoprotein (VLDL) remnants are rapidly removed from the circulation by receptor-mediated endocytosis. ApoE, the major apolipoprotein of the chylomicron in the brain, binds to a specific receptor and is essential for the normal catabolism of triglyceride-rich lipoprotein constituents. Defects in apolipoprotein E result in familial dysbetalipoproteinemia, or type III hyperlipoproteinemia (HLP III), in which increased plasma cholesterol and triglycerides are the consequence of impaired clearance of chylomicron and VLDL remnants (Mahley et al., 1999). In the brain, lipidated apoE binds aggregated in a isoform-speciflc manner, apoE4 being much more effective than the other forms,... 

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. 

Fic. 11. Effect of receptor-binding-defective forms of apolipoprotein E on the hepatic clearance of plasma lipoproteins. Defective forms of apoE result in reduced clearance of chylomicron remnants, VLDLs, and IDLs and their accumulation in plasma. The chylomicron remnants and VLDLs are enriched in cholesteryl esters as the result of CETP activity, and together they constitute the /3-VLDLs, which are a hallmark of type 111 hyperlipoproteinemia. A block in the conversion of IDLs to LDLs by hepatic lipase by the presence of an abnormal apoE form also is indicated. 

Abnormal lipoproteins are produced under various metabolic conditions. P-VLDL, a triglyceride-depleted, cholesterol-enriched form of VLDL, accumulates in the plasma of cholesterol-fed animals [13,14] or of humans with type III hyperlipoproteinemia [15]. In patients with this disease, the accumulation of j8-VLDL is believed to be due to incomplete clearance of chylomicron remnants by the liver. Slow turnover of remnants allows them to accumulate cholesteryl esters and thus to evolve into j8-VLDL particles [16,17]. -VLDL (density <1.006 g/ml, j8-electro-phoretic mobility) contain both apo-B and apo-E and may play a significant role in the formation of atherosclerotic foam cells [18]. 

While these recent studies indicate the requirement for non-receptor-mediated steps in the overall clearance pathways for triacylglycerol-rich lipoproteins, the ultimate uptake occurs by endocytotic mechanisms involving specific receptors. Studies in a variety of experimental systems predicted that the removal of chylomicron remnants occurs independent of the LDL receptor, despite the presence of apo E on these particles. Accordingly, individuals with homozygous FH, who lack functional LDL receptors, show no signs of delayed clearance of chylomicron remnants. 

Reduced delivery of intestinal cholesterol to the liver by chylomicron remnants stimulates expression of the hepatic genes regnlating LDL-receptor expression and cholesterol biosynthesis. The greater expression of hepatic LDL receptors enhances LDL-C clearance from the plasma. 

Cortner, J.A. et al. (1987). Kinetics of chylomicron remnant clearance in normal and hyper-lipoproteinemic subjects, J. Lipid Res., 28, 195. 

It is now accepted that increased postprandial lipemia is directly related to an increased rate of progression of atherosclerosis and increased risk of CHD (50,51). The degree of postprandial hypertriglyceridemia in patients with CHD is due to impaired TG clearance after a standardized fatty meal (52). Exaggerated lipemia is common in patients with CHD, and peak lipemia may occur 8 h after the fatty meal instead of the usual 3 h. Postprandial lipemia promotes the formation of chylomicron remnants (52,53). Indeed, a diet low in fat, in particular saturated fat, reduces the levels of chylomicron remnants in humans (54). The composition of the fatty meal is also important, and fish oil fatty acids may be less Upemic (54,55). 

Weintraub,M.S.,Grosskopf, I.,Rassin,T.,Mitler, H.,Charach, G., Rotmensch, H.H., Liron, M., Rubinstein, A., and laina, A. (1996) Clearance of Chylomicron Remnants in Normolipidaemic Patients with Coronary Heart Disease Case Control Study over Three Yeats, Br. Med. J.312,935-939. 

Williams, C.M. (1998) Dietary Interventions Affecting Chylomicron and Chylomicron Remnant Clearance, Atherosclerosis 141(Suppl. i),S87-S92. 

Ascorbate supplementation prevents the exacerbation of CVD associated with hypertriglyceridemia. Type III hyperlipidemia, and related disorders by stimulating lipoprotein lipases and thereby enabling a normal catabolism of triglyceride-rich lipoproteins." Ascorbate prevents the oxidative modification of these lipoproteins, their uptake by scavenger cells and foam cell formation. Moreover, we propose here that, analogous to the LDL receptor, ascorbate also increases the expression of the receptors involved in the metabolic clearance of triglyceride-rich lipoproteins, such as the chylomicron remnant receptor. 

Scheme 113.1 Schematic overview of cholesterol metabolism and main proposed mechanisms of action of phytosterols. 1. The absorption of dietary and/or biliary cholesterol is reduced by competition with PS for incorporation into mixed micelles. 2. Esterification of free cholesterol in the enterocyte is reduced by competition with PS for ACAT-2 enzyme. 3. Upregulation of the heterodimer ABCG5/G8 by PS can increase intestinal and hepato-biliar secretion. 4. Upregulation of ABCAl by PS can increase the incorporation of sterols into nascent HDL. 5. Increased cholesterol excretion via TICE. 6. Although it is not directly mediated by PS, the lower levels of hepatic cholesterol can lead to a lower VLDL secretion and upregulation of LDL receptor, which improves the clearance of plasma cholesterol. Abbreviations FC free cholesterol, CE cholesterol esters, ACAT-2 Acyl-CoA cholesterol O-acyltransferase 2, CM chylomicron, CMR chylomicron remnant, TICE transintestinal cholesterol efflux, LDL low-density lipoprotein, IDL intermediate-density lipoprotein, HDL high-density lipoprotein...

Apo-E An apolipoprotein principally associated with VLDL and chylomicrons responsible for the receptor-mediated clearance of IDL and chylomicron remnants. It is a ligand for most members of the LDL receptor superfamily. The apo-E4 isoform is associated with increased risk of Azheimer s disease. 

Whether or not a particle carries apo-B48 or apo-BIOO has physiological importance. The carboxy-terminal half of apo-B is required for receptor recognition. Thus, apo-BIOO can bind to cellular receptors (described below) apo-B48 cannot. For this reason, chylomicron remnants cannot be cleared from the circulation via apo-B48. Instead, chylomicron remnant clearance is mediated by another receptor ligand, apo-E. Indeed, genetic deficiency of apo-E leads to massive accumulation of cholesterol ester-rich chylomicron remnants and IDL in the bloodstream. 

Patients lacking the LDL receptor do not accumulate chylomicron remnants in the bloodstream. Since chylomicron remnant clearance is mediated by apo-E, it has been postulated that a separate receptor is responsible for chylomicron remnant clearance, a receptor that, in contrast to the LDL receptor, binds to apo-E, but not to apo-BlOO. Several additional members of the LDL receptor family have been identified (Table V). The first of these, the LRP, participates in chylomicron remnant clearance and plays a major role in that process when the LDL receptor is absent or dysfunctional. 

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