Single repeat deletion in ApoA-I blocks cholesterol esterification and results in rapid catabolism of delta6 and wild-type ApoA-I in transgenic mice.
Single repeat deletion in ApoA-I blocks cholesterol esterification and results in rapid catabolism of delta6 and wild-type ApoA-I in transgenic mice.
复制标题
ApoA-I 中的单次重复缺失可阻止胆固醇酯化，并导致转基因小鼠中 delta6 和野生型 ApoA-I 快速分解代谢。
DOI：
10.1074/jbc.275.16.12156
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发表时间：
2000
期刊：
影响因子：
--
通讯作者：
Landrum,M
中科院分区：
文献类型：
--
作者：
Sorci-Thomas,MG;Thomas,M;Curtiss,L;Landrum,M
The deletion mutation Δ6 apolipoprotein A-I lacks residues 143–164 or repeat 6 in the mature apoA-I protein.In vitrostudies show this mutation dramatically reduces the rate of lecithin:cholesterol acyltransferase (LCAT) catalyzed cholesterol esterification. The present study was initiated to investigate the effect of this mutation onin vivohigh density lipoprotein (HDL) cholesterol esterification and metabolism. Transgenic mice expressing human Δ6 apoA-I (TgΔ6 +/+) were created and then crossed with apoA-I knockout mice (−/−) to generate mice expressing only human Δ6 apoA-I (TgΔ6 −/−). Human Δ6 apoA-I was associated with homogeneous sized α-HDL, when wild-type mouse apoA-I was present (in TgΔ6 +/+ and +/− mice). However, in the absence of endogenous mouse apoA-I, Δ6 apoA-I was found exclusively in cholesterol ester-poor HDL, and lipid-free HDL fractions. This observation coincides with the 6-fold lower cholesterol ester mass in TgΔ6 −/− mouse plasma compared with control. Structural studies show that despite the structural perturbation of a domain extending from repeat 5 to repeat 8 (137–178), Δ6 apoA-I binds to spherical unilamellar vesicles with only 2-fold less binding affinity. In summary, these data show a domain corresponding to apoA-I repeat 6 is responsible for providing an essential conformation for LCAT catalyzed generation of cholesterol esters. Deletion of apoA-I repeat 6 not only blocks normal levels of cholesterol esterification but also exerts a dominant inhibition on the ability of wild-type apoA-I to activate LCATin vivo.
