Novel ENU-induced point mutation in scavenger receptor class B, member 1, results in liver specific loss of SCARB1 protein.
Novel ENU-induced point mutation in scavenger receptor class B, member 1, results in liver specific loss of SCARB1 protein.
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DOI：
10.1371/journal.pone.0006521
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发表时间：
2009-08-05
期刊：
影响因子：
3.7
通讯作者：
Rader DJ
中科院分区：
文献类型：
--
作者：
Stylianou IM;Svenson KL;VanOrman SK;Langle Y;Millar JS;Paigen B;Rader DJ
心血管疾病（CVD）是全世界人群过早死亡的最大原因。循环血浆脂质水平，特别是高水平的LDL或低水平的HDL，是对CVD易感性的预测。清道夫受体B类成员1（SCARB 1）是肝脏和类固醇生成组织选择性摄取HDL胆固醇的主要受体。肝脏SCARB 1影响血浆HDL-胆固醇水平，对胆固醇逆向转运至关重要。在这里，我们描述了一个新的N-乙基-N-亚硝基脲（ENU）诱导的Scarb 1基因点突变的C57 BL/6 J背景中确定的映射。该突变位于细胞外环中高度保守的氨基酸中，并导致异亮氨酸转化为天冬酰胺（I179 N）。纯合子突变小鼠表达正常的Scarb 1 mRNA水平，并具有生育能力。SCARB 1蛋白水平在肝脏中显著降低（约90%），但在类固醇生成组织中不降低。由于HDL胆固醇酯选择性摄取减少，这导致血浆HDL水平增加约70%。Pdzk 1基因敲除小鼠与该突变体一样具有SCARB 1蛋白的肝脏特异性减少;然而，对突变的体外分析表明，该突变体中SCARB 1蛋白的调节不依赖于PDZK 1。这种新的Scarb 1模型可能有助于我们进一步理解SCARB 1的翻译后和组织特异性调节，这可能有助于提高功能性HDL的重要临床目标。
Cardiovascular disease (CVD) is the largest cause of premature death in human populations throughout the world. Circulating plasma lipid levels, specifically high levels of LDL or low levels of HDL, are predictive of susceptibility to CVD. The scavenger receptor class B member 1 (SCARB1) is the primary receptor for the selective uptake of HDL cholesterol by liver and steroidogenic tissues. Hepatic SCARB1 influences plasma HDL-cholesterol levels and is vital for reverse cholesterol transport. Here we describe the mapping of a novel N-ethyl-N-nitrosourea (ENU) induced point mutation in the Scarb1 gene identified in a C57BL/6J background. The mutation is located in a highly conserved amino acid in the extracellular loop and leads to the conversion of an isoleucine to an asparagine (I179N). Homozygous mutant mice express normal Scarb1 mRNA levels and are fertile. SCARB1 protein levels are markedly reduced in liver (∼90%), but not in steroidogenic tissues. This leads to ∼70% increased plasma HDL levels due to reduced HDL cholesteryl ester selective uptake. Pdzk1 knockout mice have liver-specific reduction of SCARB1 protein as does this mutant; however, in vitro analysis of the mutation indicates that the regulation of SCARB1 protein in this mutant is independent of PDZK1. This new Scarb1 model may help further our understanding of post-translational and tissue-specific regulation of SCARB1 that may aid the important clinical goal of raising functional HDL.
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影响因子：
3.3
作者：
Concepcion, D;Seburn, KL;Hamilton, BA
通讯作者：
Hamilton, BA
DOI：
10.1161/01.atv.0000104027.52895.d7
发表时间：
2004-01-01
影响因子：
8.7
作者：
Ishimori, N;Li, RH;Paigen, B
通讯作者：
Paigen, B
影响因子：
8.7
作者：
Huszar, D;Varban, ML;Tall, AR
通讯作者：
Tall, AR
影响因子：
2.5
作者：
Colinayo, VV;Qiao, JH;Drake, TA
通讯作者：
Drake, TA
影响因子：
16.2
作者：
Chevesich, J;Kreuz, AJ;Montell, C
通讯作者：
Montell, C