The Carboxy-Terminal Region of apoA-I Is Required for the ABCA1-Dependent Formation of -HDL But Not Pre
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- 作者：Angeliki Chroni ; Georgios Koukos ; Adelina Duka ; Vassilis I. Zannis
- 刊名：Biochemistry
- 出版年：2007
- 出版时间：May 15, 2007
- 年：2007
- 卷：46
- 期：19
- 页码：5697 - 5708
- 全文大小：771K
- 年卷期：v.46,no.19(May 15, 2007)
- ISSN：1520-4995
文摘
ATP-binding cassette transporter A-1 (ABCA1)-mediated lipid efflux to lipid-poor apolipoprotein A-I (apoA-I) results in the gradual lipidation of apoA-I. This leads to the formation of discoidalhigh-density lipoproteins (HDL), which are subsequently converted to spherical HDL by the action oflecithin:cholesterol acyltransferase (LCAT). We have investigated the effect of point mutations and deletionsin the carboxy-terminal region of apoA-I on the biogenesis of HDL using adenovirus-mediated gene transferin apoA-I-deficient mice. It was found that the plasma HDL levels were greatly reduced in mice expressingthe carboxy-terminal deletion mutants apoA-I[
(185-243)] and apoA-I[(220-243)], shown previouslyto diminish the ABCA1-mediated lipid efflux. The HDL levels were normal in mice expressing the WTapoA-I, the apoA-I[(232-243)] deletion mutant, or the apoA-I[E191A/H193A/K195A] point mutant,which promote normal ABCA1-mediated lipid efflux. Electron microscopy and two-dimensional gelelectrophoresis showed that the apoA-I[(185-243)] and apoA-I[(220-243)] mutants formed mainlypre
-HDL particles and few spherical particles enriched in apoE, while WT apoA-I, apoA-I[(232-243)], and apoA-I[E191A/H193A/K195A] formed spherical 
-HDL particles. The findings establish that(a) deletions that eliminate the 220-231 region of apoA-I prevent the synthesis of -HDL but allow thesynthesis of pre-HDL particles in vivo, (b) the amino-terminal segment 1-184 of apoA-I can promotesynthesis of pre-HDL-type particles in an ABCA1-independent process, and (c) the charged residues inthe 191-195 region of apoA-I do not influence the biogenesis of HDL.
(185-243)] and apoA-I[(220-243)], shown previouslyto diminish the ABCA1-mediated lipid efflux. The HDL levels were normal in mice expressing the WTapoA-I, the apoA-I[(232-243)] deletion mutant, or the apoA-I[E191A/H193A/K195A] point mutant,which promote normal ABCA1-mediated lipid efflux. Electron microscopy and two-dimensional gelelectrophoresis showed that the apoA-I[(185-243)] and apoA-I[(220-243)] mutants formed mainlypre-HDL particles and few spherical particles enriched in apoE, while WT apoA-I, apoA-I[(232-243)], and apoA-I[E191A/H193A/K195A] formed spherical -HDL particles. The findings establish that(a) deletions that eliminate the 220-231 region of apoA-I prevent the synthesis of -HDL but allow thesynthesis of pre-HDL particles in vivo, (b) the amino-terminal segment 1-184 of apoA-I can promotesynthesis of pre-HDL-type particles in an ABCA1-independent process, and (c) the charged residues inthe 191-195 region of apoA-I do not influence the biogenesis of HDL.