title: Absence of hyperlipidemia in LDL receptor-deficient mice having apolipoprotein B100 without the putative receptor-binding sequences.
abstract: OBJECTIVE
  To examine the effects of apoB100 structure, specifically a mutation in the LDLr binding region, on the production of LDL and development of atherosclerosis in vivo.
  
  
  RESULTS
  Ldlr(-/-)Apobec1(-/-) mice lacking the LDLR and apoB editing enzyme accumulated LDL in plasma and developed severe atherosclerosis when they had wild-type apoB100. In marked contrast, in Ldlr(-/-)Apobec1(-/-) mice carrying the Apob100-beta mutation, in the 2 putative LDLR-binding domains of apoB prevented both LDL accumulation and atherosclerosis. Intestinal absorption of lipids and triglyceride secretion from the liver were not affected. However, the VLDL particles with apoB100-beta were larger in volume by about 70%, and carried approximately four times as much apoE per particle. ApoB100-beta synthesis rate in the primary hepatocytes was normal, but its intracellular degradation was enhanced. Additionally, mutant apoB100 VLDL cleared from the circulation more quickly in vivo through apoE-LRP-mediated mechanism than VLDL with wild-type apoB100. In contrast, uptake of the 2 VLDL by macrophages were not different.
  
  
  CONCLUSIONS
  While conformational change to apoB100 during conversion of VLDL to LDL exposes LDLR binding domains and facilitates LDLR-mediated lipoprotein clearance, it may also inhibit LRP-mediated VLDL uptake and contribute to LDL accumulation in familial hypercholesterolemia.
authors.affiliation: Department of Pathology and Laboratory Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7525, USA.
authors.forename: Lance A
authors.initials: LA
authors.lastname: Johnson
authors.forename: Michael K
authors.initials: MK
authors.lastname: Altenburg
authors.forename: Rosemary L
authors.initials: RL
authors.lastname: Walzem
authors.forename: Lori T
authors.initials: LT
authors.lastname: Scanga
authors.forename: Nobuyo
authors.initials: N
authors.lastname: Maeda
mesh_terms: D000071479:APOBEC-1 Deaminase; D000818:Animals; D053299:Apolipoprotein B-100 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D001665:Binding Sites; D003564:Cytidine Deaminase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D004041:Dietary Fats; D004195:Disease Models, Animal; D022781:Hepatocytes / Q000378:metabolism; D006949:Hyperlipidemias / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D008077:Lipoproteins, LDL / Q000378:metabolism; D008079:Lipoproteins, VLDL / Q000378:metabolism; D017737:Macrophages, Peritoneal / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation; D010316:Particle Size; D011485:Protein Binding; D011487:Protein Conformation; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors
chemical_list: D053299:Apolipoprotein B-100; D004041:Dietary Fats; D008077:Lipoproteins, LDL; D008079:Lipoproteins, VLDL; D011973:Receptors, LDL; D000071479:APOBEC-1 Deaminase; C000605090:Apobec1 protein, mouse; D003564:Cytidine Deaminase