Sphingosine kinase-2 prevents macrophage cholesterol accumulation and atherosclerosis by stimulating autophagic lipid degradation
Sphingosine kinase-2 prevents macrophage cholesterol accumulation and atherosclerosis by stimulating autophagic lipid degradation
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DOI：
10.1038/s41598-019-54877-6
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发表时间：
2019-12-04
影响因子：
4.6
通讯作者：
Takuwa, Yoh
中科院分区：
文献类型：
--
作者：
Ishimaru, Kazuhiro;Yoshioka, Kazuaki;Takuwa, Yoh
动脉粥样硬化是缺血性冠心病的主要原因，其特征在于血管壁中的胆固醇积聚巨噬细胞的浸润。尽管鞘脂作为膜成分和脂质介质参与动脉粥样硬化，但鞘脂在动脉粥样硬化中的确切作用仍然难以捉摸。在这里，我们发现鞘氨醇激酶-2（SphK 2）而不是SphK 1的遗传缺陷会导致ApoE缺陷小鼠动脉粥样硬化病变的形成。骨髓嵌合体实验表明，骨髓来源的细胞中表达的SphK 2的参与。在巨噬细胞中，SphK 2（该细胞类型中的主要SphK同种型）的缺乏导致细胞鞘氨醇和神经酰胺的增加。SphK 2缺陷型巨噬细胞具有含脂滴的自噬体和自溶酶体的增加以及通过自噬的脂滴的有缺陷的溶酶体降解，其中溶酶体中的管腔酸性环境和蛋白水解活性受损。SphK 2缺陷小鼠中SphK 1的转基因过表达挽救了动脉粥样硬化的加重以及巨噬细胞中自噬体和溶酶体的异常，并减少了鞘氨醇，这表明两种SphKs的作用至少部分重叠。综上所述，这些结果表明，SphK 2是必需的自噬体和溶酶体介导的细胞内脂滴的catalysis，以阻止动脉粥样硬化的发展，因此，SphK 2可能是一个新的治疗动脉粥样硬化的目标。
Atherosclerosis is the major cause of ischemic coronary heart diseases and characterized by the infiltration of cholesterol-accumulating macrophages in the vascular wall. Although sphingolipids are implicated in atherosclerosis as both membrane components and lipid mediators, the precise role of sphingolipids in atherosclerosis remains elusive. Here, we found that genetic deficiency of sphingosine kinase-2 (SphK2) but not SphK1 aggravates the formation of atherosclerotic lesions in mice with ApoE deficiency. Bone marrow chimaera experiments show the involvement of SphK2 expressed in bone marrow-derived cells. In macrophages, deficiency of SphK2, a major SphK isoform in this cell type, results in increases in cellular sphingosine and ceramides. SphK2-deficient macrophages have increases in lipid droplet-containing autophagosomes and autolysosomes and defective lysosomal degradation of lipid droplets via autophagy with an impaired luminal acidic environment and proteolytic activity in the lysosomes. Transgenic overexpression of SphK1 in SphK2-deficient mice rescued aggravation of atherosclerosis and abnormalities of autophagosomes and lysosomes in macrophages with reductions of sphingosine, suggesting at least partial overlapping actions of two SphKs. Taken together, these results indicate that SphK2 is required for autophagosome- and lysosome-mediated catabolism of intracellular lipid droplets to impede the development of atherosclerosis; therefore, SphK2 may be a novel target for treating atherosclerosis.