Modulation of sphingosine 1‐phosphate by hepatobiliary cholesterol handling
Modulation of sphingosine 1‐phosphate by hepatobiliary cholesterol handling
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DOI：
10.1096/fj.202001397r
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发表时间：
2020-09
期刊：
影响因子：
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通讯作者：
M. Kurano;K. Tsukamoto;M. Hara;K. Tsuneyama;Takako Nishikawa;H. Ikeda;Y. Yatomi
中科院分区：
文献类型：
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作者：
M. Kurano;K. Tsukamoto;M. Hara;K. Tsuneyama;Takako Nishikawa;H. Ikeda;Y. Yatomi
众所周知，由尼曼匹克C1样1蛋白（NPC 1 L1）和ABCG 5/8介导的肝胆胆固醇处理有助于胆固醇的稳态。我们试图阐明肝胆胆固醇处理对鞘脂和溶血磷脂稳态的影响，尤其是1-磷酸鞘氨醇（S1 P）。我们在小鼠肝脏中诱导NPC 1 L1或ABCG 5/8的过表达。肝脏NPC 1 L1过表达增加了血浆和肝脏S1 P水平，而降低了胆汁S1 P水平，所有这些变化均被依折麦布抑制。HDL激活内皮细胞中Akt的能力通过肝NPC 1 L1过表达而增强。使用外源性S1 P类似物C17 S1 P进行的体外和体内研究证实了NPC 1 L1介导的S1 P转运。载脂蛋白M（apoM）的上调参与这些调制，虽然apoM是不必要的这些调制。此外，在ABCG 5/8过表达小鼠中也观察到血浆S1 P水平的升高依赖于血浆apoM水平的升高。对于其他鞘脂和溶血磷脂，神经酰胺类似地被NPC 1 L1调节为S1 P，而其他脂质则受到NPC 1 L1或ABCG 5/8的不同影响。肝胆胆固醇处理也可能调节功能性脂质，如S1 P。
Hepatobiliary cholesterol handling, mediated by Niemann‐Pick C1‐like 1 protein (NPC1L1) and ABCG5/8, is well‐known to contribute to the homeostasis of cholesterol. We attempted to elucidate the impact of hepatobiliary cholesterol handling on the homeostasis of sphingolipids and lysophospholipids, especially sphingosine 1‐phosphate (S1P). We induced the overexpression of NPC1L1 or ABCG5/8 in the mouse liver. Hepatic NPC1L1 overexpression increased the plasma and hepatic S1P levels, while it decreased the biliary S1P levels, and all of these changes were inhibited by ezetimibe. The ability of HDL to activate Akt in the endothelial cells was augmented by hepatic NPC1L1 overexpression. NPC1L1‐mediated S1P transport was confirmed by both in vitro and in vivo studies conducted using C17S1P, an exogenous S1P analog. Upregulation of apolipoprotein M (apoM) was involved in these modulations, although apoM was not necessary for these modulations. Moreover, the increase in the plasma S1P levels also observed in ABCG5/8‐overexpressing mice was dependent on the elevation of the plasma apoM levels. In regard to other sphingolipids and lysophospholipids, ceramides were similarly modulated by NPC1L1 to S1P, while other lipids were differently influenced by NPC1L1 or ABCG5/8 from S1P. Hepatobiliary cholesterol handling might also regulate the functional lipids, such as S1P.