Liver Aging and Pseudocapillarization in a Werner Syndrome Mouse Model
Liver Aging and Pseudocapillarization in a Werner Syndrome Mouse Model
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DOI：
10.1093/gerona/glt169
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发表时间：
2014-09-01
影响因子：
5.1
通讯作者：
Lebel, Michel
中科院分区：
文献类型：
--
作者：
Cogger, Victoria C.;Svistounov, Dmitri;Lebel, Michel
Werner综合征是一种以人类过早动脉粥样硬化、糖尿病、癌症和死亡为特征的早衰综合征。通过删除小鼠Wrn同源基因（Wrn(Delta hel/Delta hel)）的RecQ解旋酶结构域创建的敲除小鼠模型非常有趣，因为它会导致动脉粥样硬化和高甘油三酯血症，以及与肝脏衰老和正弦变化相关的疾病。在这里，我们发现wn （Delta hel/Delta hel）小鼠表现出细胞外基质增加、脱窗、开窗直径减小以及肝窦内皮细胞炎症标志物的变化，与年龄相关的假毛细血管化一致。此外，与野生型小鼠相比，肝细胞更大，脂褐素沉积增加，核形态异常更频繁，线粒体数量减少，线粒体直径增加。wn （Delta hel/Delta hel）小鼠也有线粒体功能改变和细胞核改变。微阵列数据显示，Wrn（Delta hel/Delta hel）基因型不影响离体肝细胞或肝窦内皮细胞内许多基因的表达。这项研究表明，wn （Delta hel/Delta hel）小鼠加速了典型的与年龄相关的肝脏变化，包括假毛细血管形成。这证实了肝窦假毛细血管化是各种衰老模型的一致特征。此外，这表明DNA修复可能与肝脏的正常衰老变化有关。
Werner syndrome is a progeric syndrome characterized by premature atherosclerosis, diabetes, cancer, and death in humans. The knockout mouse model created by deletion of the RecQ helicase domain of the mouse Wrn homologue gene (Wrn(Delta hel/Delta hel)) is of great interest because it develops atherosclerosis and hypertriglyceridemia, conditions associated with aging liver and sinusoidal changes. Here, we show that Wrn(Delta hel/Delta hel) mice exhibit increased extracellular matrix, defenestration, decreased fenestration diameter, and changes in markers of liver sinusoidal endothelial cell inflammation, consistent with age-related pseudocapilliarization. In addition, hepatocytes are larger, have increased lipofuscin deposition, more frequent nuclear morphological anomalies, decreased mitochondria number, and increased mitochondrial diameter compared to wild-type mice. The Wrn(Delta hel/Delta hel) mice also have altered mitochondrial function and altered nuclei. Microarray data revealed that the Wrn(Delta hel/Delta hel) genotype does not affect the expression of many genes within the isolated hepatocytes or liver sinusoidal endothelial cells. This study reveals that Wrn(Delta hel/Delta hel) mice have accelerated typical age-related liver changes including pseudocapillarization. This confirms that pseudocapillarization of the liver sinusoid is a consistent feature of various aging models. Moreover, it implies that DNA repair may be implicated in normal aging changes in the liver.