Zhao Xiaojing, Gao Mingming, He Jinhan, Zou Liangqiang, Lyu Ying, Zhang Ling, Geng Bin, Liu George, Xu Guoheng
Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Beijing, China.
The Key Laboratory of Molecular Cardiovascular Sciences, the Ministry of Education, Beijing, China.
PLoS One. 2015 Apr 9;10(4):e0123738. doi: 10.1371/journal.pone.0123738. eCollection 2015.
The objective of this study is to determine the role of perilipin 1 (Plin1) in whole body or bone marrow-derived cells on atherogenesis.
Accumulated evidence have indicated the role of Plin1 in atherosclerosis, however, these findings are controversial. In this study, we showed that Plin1 was assembled and colocalized with CD68 in macrophages in atherosclerotic plaques of ApoE-/- mice. We further found 39% reduction of plaque size in the aortic roots of Plin1 and ApoE double knockout (Plin1-/-ApoE-/-) females compared with ApoE-/- female littermates. In order to verify whether this reduction was macrophage-specific, the bone marrow cells from wild-type or Plin1 deficient mice (Plin1-/-) were transplanted into LDL receptor deficient mice (LDLR-/-). Mice receiving Plin1-/- bone marrow cells showed also 49% reduction in aortic atherosclerotic lesions compared with LDLR-/- mice received wild-type bone marrow cells. In vitro experiments showed that Plin1-/- macrophages had decreased protein expression of CD36 translocase and an enhanced cholesterol ester hydrolysis upon aggregated-LDL loading, with unaltered expression of many other regulators of cholesterol metabolism, such as cellular lipases, and Plin2 and 3. Given the fundamental role of Plin1 in protecting LD lipids from lipase hydrolysis, it is reasonably speculated that the assembly of Plin1 in microphages might function to reduce lipolysis and hence increase lipid retention in ApoE-/- plaques, but this pro-atherosclerotic property would be abrogated on inactivation of Plin1.
Plin1 deficiency in bone marrow-derived cells may be responsible for reduced atherosclerotic lesions in the mice.
本研究的目的是确定脂滴包被蛋白1（Plin1）在全身或骨髓来源细胞中对动脉粥样硬化形成的作用。
越来越多的证据表明Plin1在动脉粥样硬化中发挥作用，然而，这些发现存在争议。在本研究中，我们发现Plin1在载脂蛋白E基因敲除（ApoE-/-）小鼠动脉粥样硬化斑块中的巨噬细胞中与CD68组装并共定位。我们进一步发现，与ApoE-/-雌性同窝小鼠相比，Plin1和ApoE双敲除（Plin1-/-ApoE-/-）雌性小鼠主动脉根部的斑块大小减少了39%。为了验证这种减少是否具有巨噬细胞特异性，将野生型或Plin1缺陷小鼠（Plin1-/-）的骨髓细胞移植到低密度脂蛋白受体缺陷小鼠（LDLR-/-）中。与接受野生型骨髓细胞的LDLR-/-小鼠相比，接受Plin1-/-骨髓细胞的小鼠主动脉粥样硬化病变也减少了49%。体外实验表明，Plin1-/-巨噬细胞在聚集低密度脂蛋白负载时，CD36转位酶的蛋白表达降低，胆固醇酯水解增强，而许多其他胆固醇代谢调节因子，如细胞脂肪酶、Plin2和Plin3的表达未改变。鉴于Plin1在保护低密度脂蛋白脂质免受脂肪酶水解方面的基本作用，合理推测Plin1在巨噬细胞中的组装可能起到减少脂解作用，从而增加ApoE-/-斑块中的脂质潴留，但这种促动脉粥样硬化特性在Plin1失活时会被消除。
骨髓来源细胞中Plin1的缺乏可能是小鼠动脉粥样硬化病变减少的原因。
