Influence of PDZK1 on lipoprotein metabolism and atherosclerosis
Influence of PDZK1 on lipoprotein metabolism and atherosclerosis
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DOI：
10.1016/j.bbadis.2008.02.004
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发表时间：
2008-05-01
影响因子：
6.2
通讯作者：
Krieger, Monty
中科院分区：
文献类型：
--
作者：
Kocher, Olivier;Yesilaltay, Ayce;Krieger, Monty
PDZK 1是含有四个PDZ蛋白相互作用结构域的支架蛋白，其结合许多膜转运蛋白的羧基末端，包括离子通道（例如，CFTR）和细胞表面受体。其中之一，HDL受体，清道夫受体B类I型（SR-BI），表现出对PDZK 1的表达和活性的显著的组织特异性依赖。在PDZK 1基因敲除（KO）小鼠中，肝脏中SR-BI蛋白表达显著降低（接近95%），但类固醇生成组织或骨髓或脾源性巨噬细胞或肺源性内皮细胞中的SR-BI蛋白表达未降低。由于肝脏SR-BI缺乏，PDZK 1 KO小鼠表现出以异常大的HDL颗粒中携带的血浆胆固醇升高为特征的血脂异常。在这里，我们发现PDZK 1基因的失活促进了高脂/高胆固醇饮食喂养的载脂蛋白E（apoE）基因敲除小鼠主动脉根部动脉粥样硬化的发展。然而，与SR-BI/apoE双基因敲除小鼠中的完全SR-BI缺陷不同，PDZK 1/apoE双基因敲除小鼠中的PDZK 1缺陷不会导致闭塞性冠状动脉疾病或心肌梗死的发展，这可能是因为它们的SR-BI残留表达。这些发现表明，在小鼠模型中，脂蛋白受体正常表达所必需的衔接蛋白的缺乏促进动脉粥样硬化。他们还将PDZK 1定义为蛋白质家族的一员，该蛋白质家族通过维持正常的脂蛋白代谢来预防心血管疾病。(c)2008 Elsevier B. V.保留所有权利。
PDZK1 is a scaffold protein containing four PDZ protein interaction domains, which bind to the carboxy termini of a number of membrane transporter proteins, including ion channels (e.g., CFTR) and cell surface receptors. One of these, the HDL receptor, scavenger receptor class B type I (SR-BI), exhibits a striking, tissue-specific dependence on PDZK1 for its expression and activity. In PDZK1 knockout (KO) mice there is a marked reduction of SR-BI protein expression (similar to 95%) in the liver, but not in steroidogenic tissues or, as we show in this report, in bone marrow- or spleen-derived macrophages, or lung-derived endothelial cells. Because of hepatic SR-BI deficiency, PDZK1 KO mice exhibit dyslipidemia characterized by elevated plasma cholesterol carried in abnormally large HDL particles. Here, we show that inactivation of the PDZK1 gene promotes the development of aortic root atherosclerosis in apolipoprotein E (apoE) KO mice fed with a high fat/high cholesterol diet. However, unlike complete SR-BI-deficiency in SR-BI/apoE double KO mice, PDZK1 deficiency in PDZK1/apoE double knockout mice did not result in development of occlusive coronary artery disease or myocardial infarction, presumably because of their residual expression of SR-BI. These findings demonstrate that deficiency of an adaptor protein essential for normal expression of a lipoprotein receptor promotes atherosclerosis in a murine model. They also define PDZK1 as a member of the family of proteins that is instrumental in preventing cardiovascular disease by maintaining normal lipoprotein metabolism. (c) 2008 Elsevier B.V. All rights reserved.