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 Hypertriglyceridemi
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- 作者：Angeliki Chroni ; Horng-Yuan Kan ; Kyriakos E. Kypreos ; Irina N. Gorshkova ; Adelina Shkodrani ; and Vassilis I. Zannis
- 刊名：Biochemistry
- 出版年：2004
- 出版时间：August 17, 2004
- 年：2004
- 卷：43
- 期：32
- 页码：10442 - 10457
- 全文大小：290K
- 年卷期：v.43,no.32(August 17, 2004)
- ISSN：1520-4995
文摘
Hypertriglyceridemia is a common pathological condition in humans of mostly unknownetiology. Here we report induction of dyslipidemia characterized by severe hypertriglyceridemia as aresult of point mutations in human apolipoprotein A-I (apoA-I). Adenovirus-mediated gene transfer inapoA-I-deficient (apoA-I-/-) mice showed that mice expressing an apoA-I[E110A/E111A] mutant hadcomparable hepatic mRNA levels with WT controls but greatly increased plasma triglyceride and elevatedplasma cholesterol levels. In addition, they had decreased apoE and apoCII levels and increased apoB48levels in very low-density lipoprotein (VLDL)/intermediate-density lipoprotein (IDL). Fast protein liquidchromatography (FPLC) analysis of plasma showed that most of cholesterol and approximately 15% ofthe mutant apoA-I were distributed in the VLDL and IDL regions and all the triglycerides in the VLDLregion. Hypertriglyceridemia was corrected by coinfection of mice with recombinant adenovirusesexpressing the mutant apoA-I and human lipoprotein lipase. Physicochemical studies indicated that theapoA-I mutation decreased the 
-helical content, the stability, and the unfolding cooperativity of bothlipid-free and lipid-bound apoA-I. In vitro functional analyses showed that reconstituted HDL (rHDL)particles containing the mutant apoA-I had 53% of scavenger receptor class B type I (SR-BI)-mediatedcholesterol efflux capacity and 37% capacity to activate lecithin:cholesterol acyltransferase (LCAT) ascompared to the WT control. The mutant lipid-free apoA-I had normal capacity to promote ATP-bindingcassette transporter A1 (ABCA1)-dependent cholesterol efflux. The findings indicate that subtle structuralalterations in apoA-I may alter the stability and functions of apoA-I and high-density lipoprotein (HDL)and may cause hypertriglyceridemia.
-helical content, the stability, and the unfolding cooperativity of bothlipid-free and lipid-bound apoA-I. In vitro functional analyses showed that reconstituted HDL (rHDL)particles containing the mutant apoA-I had 53% of scavenger receptor class B type I (SR-BI)-mediatedcholesterol efflux capacity and 37% capacity to activate lecithin:cholesterol acyltransferase (LCAT) ascompared to the WT control. The mutant lipid-free apoA-I had normal capacity to promote ATP-bindingcassette transporter A1 (ABCA1)-dependent cholesterol efflux. The findings indicate that subtle structuralalterations in apoA-I may alter the stability and functions of apoA-I and high-density lipoprotein (HDL)and may cause hypertriglyceridemia.