Infection induces a positive acute phase apolipoprotein E response from a negative acute phase gene: role of hepatic LDL receptors
Infection induces a positive acute phase apolipoprotein E response from a negative acute phase gene: role of hepatic LDL receptors
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DOI：
10.1194/jlr.m800172-jlr200
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发表时间：
2008-08-01
影响因子：
6.5
通讯作者：
Kitchens, Richard L.
中科院分区：
文献类型：
--
作者：
Li, Li;Thompson, Patricia A.;Kitchens, Richard L.
载脂蛋白E（apoE）在脂质内稳态、抗炎和宿主防御中起重要作用。由于据报道在炎症反应期间组织中的apoE mRNA水平会降低，我们惊讶地发现，在人类和小鼠的败血症感染期间，血浆apoE水平显著升高。在小鼠由脂多糖诱导的急性炎症期间也观察到了这种明显的矛盾现象：尽管肝脏、巨噬细胞和肝外组织中的apoE基因表达急剧下降，但血浆apoE水平却升高了多达4倍。我们假设血浆清除率降低导致apoE水平升高。我们的分析表明，在小鼠中apoE主要与高密度脂蛋白（HDL）结合，并且apoE主要通过低密度脂蛋白受体（LDL受体）从循环中清除。急性炎症反应降低了肝脏中LDL受体的表达，并显著降低了apoE的清除率。相反，相同的炎症刺激增加了巨噬细胞中LDL受体的表达。我们的研究结果确定了一种新的急性期机制，即在apoE产生减少的情况下增加循环中的apoE水平。因此，肝脏中LDL受体表达的降低可能与巨噬细胞中LDL受体表达的升高协同作用，以促进apoE及其相关脂质向这些关键防御细胞的正向转运。
Apolipoprotein E (apoE) plays important roles in lipid homeostasis, anti-inflammation, and host defense. Since tissue apoE mRNA levels have been reported to decrease during inflammatory responses, we were surprised to find that plasma apoE levels were significantly elevated during septic infections in both humans and mice. This apparent paradox was also observed during lipopolysaccharide-induced acute inflammation in mice: plasma levels of apoE increased up to 4-fold despite sharply decreased apoE gene expression in the liver, macrophages, and extrahepatic tissues. We hypothesized that apoE levels were augmented by decreased plasma clearance. Our analysis revealed that apoE associated principally with HDL in mice and that apoE was cleared from the circulation principally via LDL receptors. The acute inflammatory response decreased LDL receptor expression in the liver and significantly reduced the rate of apoE clearance. In contrast, the same inflammatory stimuli increased LDL receptor expression in macrophages. Our results define a novel acute phase mechanism that increases circulating apoE levels as apoE production decreases. Diminished hepatic LDL receptor expression may thus cooperate with elevated LDL receptor expression in macrophages to facilitate the forward transport of apoE and its associated lipids to these key defense cells.