title: Dysfunctional HDL containing L159R ApoA-I leads to exacerbation of atherosclerosis in hyperlipidemic mice.
abstract: The mutation L159R apoA-I or apoA-I(L159R) (FIN) is a single amino acid substitution within the sixth helical repeat of apoA-I. It is associated with a dominant negative phenotype, displaying hypoalphaproteinemia and an increased risk for atherosclerosis in humans. Mice lacking both mouse apoA-I and LDL receptor (LDL(-/-), apoA-I(-/-)) (double knockout or DKO) were crossed>9 generations with mice transgenic for human FIN to obtain L159R apoA-I, LDLr(-/-), ApoA-I(-/-) (FIN-DKO) mice. A similar cross was also performed with human wild-type (WT) apoA-I (WT-DKO). In addition, FIN-DKO and WT-DKO were crossed to obtain WT/FIN-DKO mice. To determine the effects of the apoA-I mutations on atherosclerosis, groups of each genotype were fed either chow or an atherogenic diet for 12weeks. Interestingly, the production of dysfunctional HDL-like particles occurred in DKO and FIN-DKO mice. These particles were distinct with respect to size, and their enrichment in apoE and cholesterol esters. Two-dimensional gel electrophoresis indicated that particles found in the plasma of FIN-DKO mice migrated as large α(3)-HDL. Atherosclerosis analysis showed that FIN-DKO mice developed the greatest extent of aortic cholesterol accumulation compared to all other genotypes, including DKO mice which lack any apoA-I. Taken together these data suggest that the presence of large apoE enriched HDL particles containing apoA-I L159R lack the normal cholesterol efflux promoting properties of HDL, rendering them dysfunctional and pro-atherogenic. In conclusion, large HDL-like particles containing apoE and apoA-I(L159R) contribute rather than protect against atherosclerosis, possibly through defective efflux properties and their potential for aggregation at their site of interaction in the aorta. This article is part of a Special Issue entitled Advances in High Density Lipoprotein Formation and Metabolism: A Tribute to John F. Oram (1945-2010).
authors.affiliation: Department of Pathology, Section on Lipid Sciences, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA. msthomas@wakehealth.edu
authors.forename: Mary G
authors.initials: MG
authors.lastname: Sorci-Thomas
authors.forename: Manal
authors.initials: M
authors.lastname: Zabalawi
authors.forename: Manish S
authors.initials: MS
authors.lastname: Bharadwaj
authors.forename: Ashley J
authors.initials: AJ
authors.lastname: Wilhelm
authors.forename: John S
authors.initials: JS
authors.lastname: Owen
authors.forename: Bela F
authors.initials: BF
authors.lastname: Asztalos
authors.forename: Shaila
authors.initials: S
authors.lastname: Bhat
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Thomas
mesh_terms: D000818:Animals; D001011:Aorta / Q000378:metabolism / Q000473:pathology; D016632:Apolipoprotein A-I / Q000097:blood / Q000235:genetics* / Q000378:metabolism; D001053:Apolipoproteins / Q000097:blood / Q000235:genetics; D001057:Apolipoproteins E / Q000097:blood; D050197:Atherosclerosis / Q000097:blood / Q000235:genetics*; D002478:Cells, Cultured; D002784:Cholesterol / Q000097:blood; D004036:Diet, Atherogenic / Q000009:adverse effects; D005260:Female; D015870:Gene Expression; D006801:Humans; D006949:Hyperlipidemias / Q000097:blood / Q000235:genetics*; D008075:Lipoproteins, HDL / Q000097:blood / Q000235:genetics*; D008077:Lipoproteins, LDL / Q000097:blood; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008822:Mice, Transgenic; D020125:Mutation, Missense; D014280:Triglycerides / Q000097:blood
chemical_list: C505693:APOA1 protein, human; D016632:Apolipoprotein A-I; D001053:Apolipoproteins; D001057:Apolipoproteins E; D008075:Lipoproteins, HDL; D008077:Lipoproteins, LDL; D014280:Triglycerides; D002784:Cholesterol