THE ROLE OF LECITHIN - CHOLESTEROL ACYLTRANSFERASE FOR LIPOPROTEIN (A) ASSEMBLY - STRUCTURAL INTEGRITY OF LOW-DENSITY LIPOPROTEINS IS A PREREQUISITE FOR LP(A) FORMATION IN HUMAN PLASMA

Citation
E. Steyrer et al., THE ROLE OF LECITHIN - CHOLESTEROL ACYLTRANSFERASE FOR LIPOPROTEIN (A) ASSEMBLY - STRUCTURAL INTEGRITY OF LOW-DENSITY LIPOPROTEINS IS A PREREQUISITE FOR LP(A) FORMATION IN HUMAN PLASMA, The Journal of clinical investigation, 94(6), 1994, pp. 2330-2340
Citations number
55
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Medicine, Research & Experimental
ISSN journal
0021-9738
Volume
94
Issue
6
Year of publication
1994
Pages
2330 - 2340
Database
ISI
SICI code
0021-9738(1994)94:6<2330:TROL-C>2.0.ZU;2-0
Abstract
The composition of lipoproteins in the plasma of patients with LCAT de ficiency (LCAT-D) is grossly altered due to the lack of cholesteryl es ters which form the core of normal lipoproteins. When plasma from LCAT -D patients and their relatives was examined we found that nine hetero zygotes had plasma Lp(a) levels of 2-13 mg/dl whereas none of 11 affec ted homozygous individuals from different families contained detectabl e amounts of Lp(a) in their plasma. Therefore, the binding of apo(a) t o LDL density particles was studied in vitro using LDL density fractio ns prepared from patients, and recombinant apo(a) [r-apo(a)], which wa s expressed and secreted by transfected COS-7 cells. The LDL from hete rozygotes were chemically indistinguishable from normal LDL and homoge neous with regard to morphology, whereas the crude LDL floating fracti on from homozygotes consisted of a heterogeneous mixture of large vesi cles, and small spheres resembling normal LDL. The LDL density fractio n from the LCAT-D patient lacked almost completely cholesteryl esters. Incubation of LCAT-D plasma with active LCAT caused a substantial aug mentation of the original subfraction which morphologically resembled normal LDL. Using r-apo(a) and normal LDL or LDL of heterozygous indiv iduals, apoB:r-apo(a) complexes were formed when incubated at 37 degre es C in vitro for 20 h. In contrast, the total LDL floating fraction f rom a homozygous LCAT-D patient failed to form apoB:r-apo(a) complexes . After treatment with active LCAT, a significant apoB:r-apo(a) associ ation was observed with LCAT-D LDL density particles. Our data emphasi ze the importance of the integrity of LDL structure and composition fo r the formation of Lp(a). In addition, we demonstrate that the absence of LCAT activity has a fundamental impact on the regulation of plasma Lp(a) levels.