Department of Pathology, Dunedin School of Medicine, University of Otago, P.O. Box 56, Dunedin 9054, New Zealand.
Maurice Wilkins Centre for Molecular Biodiscovery, Private Bag 92019, Auckland 1142, New Zealand.
Biomed Res Int. 2018 Nov 25;2018:4963942. doi: 10.1155/2018/4963942. eCollection 2018.
Mouse models of hypercholesterolaemia have been used to identify arterial proteins involved in atherosclerosis. As the liver is extremely sensitive to dyslipidemia, one might expect major changes in the abundance of liver proteins in these models even before atherosclerosis develops.
Lipid levels were measured and a proteomic approach was used to quantify proteins in the livers of mice with an elevated low-density lipoprotein (LDL) and the presence of lipoprotein(a) [Lp(a)] but no atherosclerosis.
The livers of Lp(a) mice showed an increased triglyceride but reduced phospholipid and oxidised lipid content. Two-dimensional gel electrophoresis and mass spectrometry analysis identified 24 liver proteins with significantly increased abundance in Lp(a) mice (<0.05). A bioinformatic analysis of the 24 proteins showed the major effect was that of an enhanced antioxidant and lipid efflux response with significant increases in antioxidant (Park7, Gpx1, Prdx6, and Sod1) and lipid metabolism proteins (Fabp4, Acaa2, apoA4, and ApoA1). Interestingly, human liver cells treated with Lp(a) showed significant increases in Gpx1 and Prdx6 but not Sod1 or Park7.
The presence of human LDL and Lp(a) in mice promotes an enhanced flux of lipids into the liver which elicits an antioxidant and lipid export response before the onset of atherosclerosis. The antioxidant response can be reproduced in human liver cells treated with Lp(a).
高胆固醇血症的小鼠模型已被用于鉴定动脉粥样硬化相关的动脉蛋白。由于肝脏对血脂异常极其敏感，人们可能期望在动脉粥样硬化发生之前，这些模型中的肝脏蛋白丰度会发生重大变化。
测量血脂水平，并采用蛋白质组学方法定量测定载脂蛋白(a) [Lp(a)]升高且存在脂蛋白(a)但无动脉粥样硬化的小鼠肝脏中的蛋白质。
Lp(a)小鼠的肝脏甘油三酯增加，而磷脂和氧化脂质含量减少。二维凝胶电泳和质谱分析鉴定出 24 种肝脏蛋白在 Lp(a)小鼠中丰度显著增加（<0.05）。对 24 种蛋白质的生物信息学分析表明，主要影响是抗氧化和脂质外排反应增强，抗氧化（Park7、Gpx1、Prdx6 和 Sod1）和脂质代谢蛋白（Fabp4、Acaa2、apoA4 和 ApoA1）显著增加。有趣的是，用 Lp(a)处理的人肝细胞中 Gpx1 和 Prdx6 显著增加，但 Sod1 或 Park7 没有增加。
在小鼠中存在人 LDL 和 Lp(a) 会促进脂质大量流入肝脏，在动脉粥样硬化发生之前引发抗氧化和脂质输出反应。用 Lp(a)处理人肝细胞可以重现抗氧化反应。
