Naturally occurring and bioengineered apoA-I mutations that inhibit the conversion of discoidal to spherical HDL: the abnormal HDL phenotypes can be corrected by treatment with LCAT
- PMID: 17506726
- PMCID: PMC1948983
- DOI: 10.1042/BJ20070296
Naturally occurring and bioengineered apoA-I mutations that inhibit the conversion of discoidal to spherical HDL: the abnormal HDL phenotypes can be corrected by treatment with LCAT
Abstract
In the present study we have used adenovirus-mediated gene transfer of apoA-I (apolipoprotein A-I) mutants in apoA-I-/- mice to investigate how structural mutations in apoA-I affect the biogenesis and the plasma levels of HDL (high-density lipoprotein). The natural mutants apoA-I(R151C)Paris, apoA-I(R160L)Oslo and the bioengineered mutant apoA-I(R149A) were secreted efficiently from cells in culture. Their capacity to activate LCAT (lecithin:cholesterol acyltransferase) in vitro was greatly reduced, and their ability to promote ABCA1 (ATP-binding cassette transporter A1)-mediated cholesterol efflux was similar to that of WT (wild-type) apoA-I. Gene transfer of the three mutants in apoA-I-/- mice generated aberrant HDL phenotypes. The total plasma cholesterol of mice expressing the apoA-I(R160L)Oslo, apoA-I(R149A) and apoA-I(R151C)Paris mutants was reduced by 78, 59 and 61% and the apoA-I levels were reduced by 68, 64 and 55% respectively, as compared with mice expressing the WT apoA-I. The CE (cholesteryl ester)/TC (total cholesterol) ratio of HDL was decreased and the apoA-I was distributed in the HDL3 region. apoA-I(R160L)Oslo and apoA-I(R149A) promoted the formation of prebeta1 and alpha4-HDL subpopulations and gave a mixture of discoidal and spherical particles. apoA-I(R151C)Paris generated subpopulations of different sizes that migrate between prebeta and alpha-HDL and formed mostly spherical and a few discoidal particles. Simultaneous treatment of mice with adenovirus expressing any of the three mutants and human LCAT normalized plasma apoA-I, HDL cholesterol levels and the CE/TC ratio. It also led to the formation of spherical HDL particles consisting mostly of alpha-HDL subpopulations of larger size. The correction of the aberrant HDL phenotypes by treatment with LCAT suggests a potential therapeutic intervention for HDL abnormalities that result from specific mutations in apoA-I.
Figures
Similar articles
-
Discrete roles of apoA-I and apoE in the biogenesis of HDL species: lessons learned from gene transfer studies in different mouse models.Ann Med. 2008;40 Suppl 1:14-28. doi: 10.1080/07853890701687219. Ann Med. 2008. PMID: 18246469 Review.
-
LCAT can rescue the abnormal phenotype produced by the natural ApoA-I mutations (Leu141Arg)Pisa and (Leu159Arg)FIN.Biochemistry. 2007 Sep 18;46(37):10713-21. doi: 10.1021/bi7003203. Epub 2007 Aug 21. Biochemistry. 2007. PMID: 17711302
-
The carboxy-terminal region of apoA-I is required for the ABCA1-dependent formation of alpha-HDL but not prebeta-HDL particles in vivo.Biochemistry. 2007 May 15;46(19):5697-708. doi: 10.1021/bi602354t. Epub 2007 Apr 21. Biochemistry. 2007. PMID: 17447731 Free PMC article.
-
Role of apoA-I, ABCA1, LCAT, and SR-BI in the biogenesis of HDL.J Mol Med (Berl). 2006 Apr;84(4):276-94. doi: 10.1007/s00109-005-0030-4. Epub 2006 Feb 25. J Mol Med (Berl). 2006. PMID: 16501936 Review.
-
Substitutions of glutamate 110 and 111 in the middle helix 4 of human apolipoprotein A-I (apoA-I) by alanine affect the structure and in vitro functions of apoA-I and induce severe hypertriglyceridemia in apoA-I-deficient mice.Biochemistry. 2004 Aug 17;43(32):10442-57. doi: 10.1021/bi049782p. Biochemistry. 2004. PMID: 15301543
Cited by
-
Precision Nutrition and Cardiovascular Disease Risk Reduction: the Promise of High-Density Lipoproteins.Curr Atheroscler Rep. 2023 Oct;25(10):663-677. doi: 10.1007/s11883-023-01148-5. Epub 2023 Sep 13. Curr Atheroscler Rep. 2023. PMID: 37702886 Free PMC article. Review.
-
Association of Plasma Vitamins and Carotenoids, DNA Methylation of LCAT, and Risk of Age-Related Macular Degeneration.Nutrients. 2023 Jun 30;15(13):2985. doi: 10.3390/nu15132985. Nutrients. 2023. PMID: 37447314 Free PMC article.
-
Apolipoprotein A1-Related Proteins and Reverse Cholesterol Transport in Antiatherosclerosis Therapy: Recent Progress and Future Perspectives.Cardiovasc Ther. 2022 Jan 10;2022:4610834. doi: 10.1155/2022/4610834. eCollection 2022. Cardiovasc Ther. 2022. PMID: 35087605 Free PMC article. Review.
-
Current Therapies Focused on High-Density Lipoproteins Associated with Cardiovascular Disease.Molecules. 2018 Oct 23;23(11):2730. doi: 10.3390/molecules23112730. Molecules. 2018. PMID: 30360466 Free PMC article. Review.
-
Role of apolipoproteins, ABCA1 and LCAT in the biogenesis of normal and aberrant high density lipoproteins.J Biomed Res. 2017 Nov 4;31(6):471-85. doi: 10.7555/JBR.31.20160082. Online ahead of print. J Biomed Res. 2017. PMID: 29109329 Free PMC article.
References
-
- Zannis V. I., Kardassis D., Zanni E. E. Genetic mutations affecting human lipoproteins, their receptors and their enzymes. Adv. Hum. Genet. 1993;21:145–319. - PubMed
-
- Chroni A., Liu T., Gorshkova I., Kan H. Y., Uehara Y., von Eckardstein A., Zannis V. I. The central helices of apoA-I can promote ATP-binding cassette transporter A1 (ABCA1)-mediated lipid efflux. Amino acid residues 220-231 of the wild-type apoA-I are required for lipid efflux in vitro and high density lipoprotein formation in vivo. J. Biol. Chem. 2003;278:6719–6730. - PubMed
-
- Laccotripe M., Makrides S. C., Jonas A., Zannis V. I. The carboxyl-terminal hydrophobic residues of apolipoprotein A-I affect its rate of phospholipid binding and its association with high density lipoprotein. J. Biol. Chem. 1997;272:17511–17522. - PubMed
-
- Liu T., Krieger M., Kan H. Y., Zannis V. I. The effects of mutations in helices 4 and 6 of apoA-I on scavenger receptor class B type I (SR-BI)-mediated cholesterol efflux suggest that formation of a productive complex between reconstituted high density lipoprotein and SR-BI is required for efficient lipid transport. J. Biol. Chem. 2002;277:21576–21584. - PubMed
Publication types
MeSH terms
Substances
Grants and funding
LinkOut - more resources
Full Text Sources
Medical
Miscellaneous