Remnant receptors

LPL found on the endothelial surfaces of the blood capillaries) to produce chylomicron remnants, which are then removed from the circulation by specific remnant receptors located on parenchymal liver cells. VLDLs are secreted by the liver. Following their secretion in blood, VLDLs undergo metabolism in a way... 

P.C.N. Rensen, N. Herijgers, M.H. Netscher, S.C.J. Meskers, M. van Eck and T.J.C. van Berkel, Particle size determines the specificity of apolipoprotein E-containing triglyceride-rich emulsions for the LDL-receptor versus hepatic remnant receptor in vivo, J. Lipid Res. 38 (1997) 1070-1084. 

Chylomicron remnants, containing primarily cholesterol, apo-E and apo-B-48, are then taken up by the liver through interaction with the chylomicron remnant receptor (this recognition requires apo-E). 

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. 

Simultaneously, some of the phospholipids and the apo A apolipoproteins are transferred from the chylomicron particle onto HDL. The newly formed particle, the chylomicron remnant, contains 80% to 90% of the triglyceride content of the original chylomicron. Because of the presence of apo B-48 and apo E on its surface, the chylomicron remnant can be recognized by specific hepatic remnant receptors and internalized by endocytosis. The components of the particle are then hydrolyzed in the lysosomes. The cholesterol released can form bile acids, be incorporated into newly synthesized lipoprotein, or be stored as cholesteryl ester. Furthermore, the cholesterol from these remnants can down regulate HMG-CoA reductase, the rate-hmiting enzyme of cholesterol biosynthesis (see earlier section on cholesterol synthesis). 

During the hydrolysis of VLDL triglycerides, the C apohpoproteins are transferred back to HDL. VLDL particles are thus converted to VLDL remnants, some of which are taken up by the liver and the rest converted to smaller, denser particles called IDL. Large IDL particles, which also have several molecules of apo E, bind the hepatic remnant receptors and are removed from circulation. In humans, about 50% of IDL is removed by hepatocytes. 

Figure 26-21 Reverse cholesterol transport pathway. HDl High-density lipoproteins LDL, low-density lipoproteins tDL, intermediate-density lipoproteins HTL, hepatic lipoprotein lipase LCAT, lecithin cholesterol acyltransferase CETP, cholesteryl ester transfer protein apo E, apoiipoprotein E. Cholesterol is removed from macrophages and other arterial wall cells by an HDL-mediated process. The LCAT esterifies the cholesterol content of HDL to prevent it from reentering the ceils. Cholesterol esters are delivered to the liver by one of three pathways ( ) cholesterol esters are transferred from HDL to LDL by CETP and enter the liver through the specific LDL receptor pathway (2) cholesterol esters are selectively taken from HDL by HDL receptors and HDL particles are returned to circulation for further transport or (3) HDL have accumulated apo E and therefore the particles can enter the liver through remnant receptors, (From Gwynne JT. High density lipoprotein cholesterol levels as a marker of reverse cho/estero/ tronsport./ m j Cardiol I989 64 10G-I7G. Copyright 1989, with permission from Excerpta Medico Inc.)...

Chylomicrons, large triglyceride-rich particles containing apolipoprotein B-48, B-lOO, and E, are formed from dietary fat solubilized by bile salts in intestinal mucosal cells (Fig. 21-2). Chylomicrons normally are not present in the plasma after a fast of 12 to 14 hours and are catabolized by lipoprotein lipase (LPL), which is activated by apolipoprotein C-II, in the vascular endothelium and hepatic lipase to form chylomicron remnants. The remnants that contain apolipoprotein E (see Fig. 21-2) are taken up by the remnant receptor, which may be an LDL-receptor-related protein, in the liver. Free cholesterol is liberated intracellularly after attachment to the remnant receptor. Chylomicrons also function to deliver dietary triglyceride to skeletal muscle and adipose tissue. During the catabolism of nascent chylomicrons to remnants, triglyceride is converted to free fatty acids and apolipoproteins A-I, A-II, A-IV (free in plasma), C-I, C-II, and... 

In the capillary beds in adipose tissue, muscle tissue (especially cardiac muscle) and in lactating mammary glands, apoC-II binds to and activates lipoprotein lipase (LPL), which is bound to the endothelial surface of the capillaries by heparan sulfate. LPL hydrolyzes the TG in the core of the chylomicron to free fatty acids and glycerol. The fatty acids are taken up by the adipose or muscle cells glycerol is recycled back to the liver. In muscle, the fatty acids are oxidized to produce ATP and in adipose they are reformed into TG for storage. The TG-depleted chylomicron remnant remains in the blood stream until it binds to the chylomicron remnant receptor located on hepatocytes, a process... 

FIGURE 35-1 The miyor pathwi s involved in the metabolism of chylomicrons synthesized by the intestine and VLDL synthesized by the liver. Chylomicrons are converted to chylomicron remnants by the hydrolysis of their triglycerides by LPL. Chylomicron remnants are rapidly cleared from the plasma by the liver. Remnant receptors include die LDL receptor-related protein (LRP), LDL, and perhaps other receptors. FFA released by LPL is used by muscle tissue as an energy source or taken up and stored by adipose tissue. FFA, free fatty acid HL, hepatic lipase IDL, intermediate-density lipoproteins LDL, low-density lipoproteins LPL, lipoprotein lipase VLDL, very-low-density lipoproteins. 

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. 

The classical abnormal lipoprotein is beta-VLDL. The E-II homozygosity leads to an impaired interaction with both the remnant receptor and the B E receptor with a consequent slow catabolism of VLDL- or chylomicron remnants. Ongoing transfer of cholesteryl esters to these large particles causes an unusual lipid composition of the thus modified particles and a consequent dysequilibrium of the lipoprotein system. Large amounts of Apo-E are found in VLDL, and the concentration of LDL or better LP-B is markedly decreased. 

Apo E, a quantitatively minor apolipoprotein, is a 34-kd glycoprotein constituent of plasma triglyceride-rich lipoproteins and of HDL. The functional role of Apo E is most likely that of interaction with the remnant receptor in the liver [26]. Apo E is polymorphic, having three major isofonns separated by isoelectric focusing (Apo E2, E3, and E4). Each of the three polymorphic forms of Apo E is coded by a separate allele the alleles being inherited in a codominant fashion at a single genetic locus. 

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