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Lipoprotein Clearance Mechanisms in LDL Receptor-Deficient "Apo-B48-Only" and "Apo-B100-Only" Mice

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Lipoprotein Clearance Mechanisms in LDL Receptor-Deficient Lipoprotein clearance mechanisms in LDL receptor-deficient "Apo-B48-only" and "Apo-B100-only" mice. M M Véniant, … , J Herz, S G Young J Clin Invest. 1998;102(8):1559-1568. https://doi.org/10.1172/JCI4164. Research Article The role of the low density lipoprotein receptor (LDLR) in the clearance of apo-B48-containing lipoproteins and the role of the LDLR-related protein (LRP) in the removal of apo-B100-containing lipoproteins have not been clearly defined. To address these issues, we characterized LDLR-deficient mice homozygous for an "apo-B48-only" allele, an "apo-B100- only" allele, or a wild-type apo-B allele (Ldlr-/- Apob48/48, Ldlr-/-Apob100/100, and Ldlr-/-Apob+/+, respectively). The plasma apo-B48 and LDL cholesterol levels were higher in Ldlr-/-Apob48/48 mice than in Apob48/48 mice, indicating that the LDL receptor plays a significant role in the removal of apo-B48-containing lipoproteins. To examine the role of the LRP in the clearance of apo-B100-containing lipoproteins, we blocked hepatic LRP function in Ldlr-/-Apob100/100 mice by adenoviral-mediated expression of the receptor-associated protein (RAP). RAP expression did not change apo-B100 levels in Ldlr-/-Apob100/100 mice. In contrast, RAP expression caused a striking increase in plasma apo-B48 levels in Apob48/48 and Ldlr-/-Apob48/48 mice. These data imply that LRP is important for the clearance of apo-B48-containing lipoproteins but plays no significant role in the clearance of apo-B100-containing lipoproteins. Find the latest version: https://jci.me/4164/pdf Lipoprotein Clearance Mechanisms in LDL Receptor–Deficient “Apo-B48-only” and “Apo-B100-only” Mice Murielle M. Véniant,*‡ Constance H. Zlot,* Rosemary L. Walzem,i Vincenzo Pierotti,* Robert Driscoll,* David Dichek,*‡§ Joachim Herz,¶ and Stephen G. Young*‡§ *Gladstone Institute of Cardiovascular Disease, San Francisco, California 94141-9100; ‡Cardiovascular Research Institute and §Department of Medicine, University of California, San Francisco, California 94143; iDepartment of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, California 95616; and ¶Department of Molecular Genetics, University of Texas Southwestern Medical School, Dallas, Texas 75235-9046 Abstract sembly of chylomicrons in the intestine (2, 3). Apo-B48 is syn- thesized as a result of apo-B mRNA editing, which changes The role of the low density lipoprotein receptor (LDLR) in codon 2153 (CAA, specifying Gln) to a translational stop the clearance of apo-B48–containing lipoproteins and the codon (4). In some mammals, including mice and rats, but not role of the LDLR-related protein (LRP) in the removal of humans, the liver expresses apo-B mRNA editing activity and apo-B100–containing lipoproteins have not been clearly therefore synthesizes apo-B48 in addition to apo-B100 (5). In defined. To address these issues, we characterized LDLR- mice, approximately 70% of the hepatic apo-B transcripts deficient mice homozygous for an “apo-B48-only” allele, an code for apo-B48 (6). “apo-B100-only” allele, or a wild-type apo-B allele (Ldlr2/2 Apo-B100–containing LDL bind to and are taken up by the Apob48/48, Ldlr2/2Apob100/100, and Ldlr2/2Apob1/1, respec- LDL receptor (LDLR), in both hepatic and extrahepatic tis- tively). The plasma apo-B48 and LDL cholesterol levels sues. When the LDLR is absent or defective, as in familial hy- were higher in Ldlr2/2Apob48/48 mice than in Apob48/48 mice, percholesterolemia, the plasma levels of apo-B100 and LDL indicating that the LDL receptor plays a significant role in cholesterol are markedly elevated (7). Apo-B48 lacks the por- the removal of apo-B48–containing lipoproteins. To exam- tion of the apo-B molecule that interacts with the LDLR and ine the role of the LRP in the clearance of apo-B100–con- therefore cannot directly mediate the uptake of lipoproteins taining lipoproteins, we blocked hepatic LRP function in by the LDLR (8). However, apo-B48–containing lipoproteins Ldlr2/2Apob100/100 mice by adenoviral-mediated expression accommodate a large amount of apo-E (9), which is a ligand of the receptor-associated protein (RAP). RAP expression for both the LDLR and the LDLR-related protein (LRP) (10, did not change apo-B100 levels in Ldlr2/2Apob100/100 mice. 11). Several recent studies have suggested that the LRP plays a In contrast, RAP expression caused a striking increase in role in the removal of apo-B48–containing lipoproteins from plasma apo-B48 levels in Apob48/48 and Ldlr2/2Apob48/48 the plasma (12, 13), but the relative importance of the LRP mice. These data imply that LRP is important for the clear- and the LDLR in the uptake of apo-B48–containing lipopro- ance of apo-B48–containing lipoproteins but plays no sig- teins has never been defined precisely. nificant role in the clearance of apo-B100–containing lipo- In this study, we investigated the mechanisms for the up- proteins. (J. Clin. Invest. 1998. 102:1559–1568.) Key words: take of apo-B48– and apo-B100–containing lipoproteins by the low density lipoproteins • LDL receptor–related protein • LDLR and by the LRP. Specifically, we sought to understand mouse apo-B radioimmunoassay • LDL receptor deficiency • whether the LDLR has a significant role in the clearance of adenovirus-mediated gene transfer apo-B48–containing lipoproteins from the plasma. We also sought to determine whether the LRP, from the perspective of Introduction lipoprotein metabolism, was simply a receptor for the apo-B48– containing lipoproteins, or whether it also has a measurable The B apolipoproteins (apo-B100 and apo-B48) have been effect on the metabolism of apo-B100–containing lipoproteins. studied extensively because they play central roles in lipopro- To address these issues, we have characterized gene-targeted tein assembly, plasma lipid metabolism, and atherogenesis (1, mice that synthesize exclusively apo-B48 (“apo-B48-only” 2). Apo-B100 is essential for the assembly of very low density mice) or exclusively apo-B100 (“apo-B100-only” mice), both lipoproteins (VLDL)1 in the human liver and is virtually the in the presence and absence of LDLR expression and in the only protein component of cholesterol-rich low density lipo- presence and absence of receptor-associated protein (RAP) proteins (LDL) (3). Apo-B48, a truncated apo-B containing expression. Our studies have shown that the LDLR does play the amino-terminal portion of apo-B100, is required for the as- a significant role in the clearance of apo-B48–containing lipo- proteins, but that the LRP also has a major role. Interestingly, the LRP has no apparent role in the metabolism of apo-B100– Address correspondence to Murielle M. Véniant, Gladstone Institute of Cardiovascular Disease, P.O. Box 419100, San Francisco, CA 94141-9100. Phone: 415-826-7500; FAX: 415-285-5632; E-mail: 1. Abbreviations used in this paper: Ad-b-Gal, adenovirus containing [email protected] the cDNA for E. coli b-galactosidase; Ad-RAP, adenovirus contain- Received for publication 1 June 1998 and accepted in revised form ing the cDNA for rat receptor-associated protein; apo, apolipoprotein; 27 August 1998. FPLC, fast-performance liquid chromatography; HDL, high density li- poprotein; LDL, low density lipoprotein; LDLR, low density lipopro- The Journal of Clinical Investigation tein receptor; LRP, low density lipoprotein receptor-related protein; Volume 102, Number 8, October 1998, 1559–1568 pfu, plaque-forming unit; RAP, receptor-associated protein; RIA, ra- http://www.jci.org dioimmunoassay; VLDL, very low density lipoprotein. Mechanisms for the Clearance of Apo-B48 and Apo-B100 1559 containing lipoproteins, even when LDLR activity is absent. Raabe, S.P.A. McCormick, P. Ambroziak, L.M. McEvoy, and S. Thus, from the perspective of lipoprotein metabolism, the Young, manuscript submitted for publication]. All mice are available LRP is an “apo-B48–containing lipoprotein” receptor. from Jackson Labs.) Plasma apo-B100 levels in different groups of mice are presented as the percentage of the amount of apo-B100 in wild-type mice. Mouse apo-B100 concentrations were also measured Methods with a direct-binding “sandwich” RIA (18, 19), using two different mouse apo-B100–specific mAbs. Generation of LDLR-deficient mice that synthesize exclusively apo- Analysis of apo-B in the plasma by Western blotting. To compare B48 or apo-B100. Mice that synthesize exclusively apo-B48 (Apob48/48 the amounts of apo-B48 and apo-B100 in different plasma samples mice) or apo-B100 (Apob100/100 mice) (14) were bred with LDLR- and to judge the relative amounts of apo-B48 and apo-B100 in mouse deficient mice (Ldlr2/2) (15) to generate Ldlr2/2Apob48/48 and Ldlr2/2 plasma, we performed Western blots of polyacrylamide/SDS gel as Apob100/100 mice. (Ldlr2/2Apob48/48, Ldlr2/2Apob100/100, Apoe2/2Apob48/48, previously described (16). The intensity of the bands was quantified and Apoe2/2Apob100/100 mice are currently available from The Jack- with a GS300 transmittance/reflectance scanning densitometer and son Laboratory [Bar Harbor, ME; http://www.jax.org]). We also gen- the GS-365 data system for densitometer (Hoefer Scientific Instru- erated a third group of mice, LDLR-deficient mice homozygous for a ments, San Francisco, CA). wild-type apo-B allele (Ldlr2/2Apob1/1 mice). All three groups of Large-scale preparation of the recombinant adenovirus. A recom- mice had a similar genetic background (z 75% C57BL/6 and 25% binant adenovirus containing the cDNA for rat receptor-associated 129/sv). For some experiments, we also used apo-E–deficient mice protein (Ad-RAP) has been described previously by Willnow and co- with the targeted apo-B gene mutations (Apoe2/2Apob48/48 and Apoe2/2 workers (12). As a control, we used an adenovirus containing the Apob100/100 mice), as well as apo-E–deficient mice homozygous for a cDNA for Escherichia coli b-galactosidase (Ad-b-Gal) (20).
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