A novel role for ABCA1-generated large pre-β migrating nascent HDL in the regulation of hepatic VLDL triglyceride secretion[S]
A novel role for ABCA1-generated large pre-β migrating nascent HDL in the regulation of hepatic VLDL triglyceride secretion[S]
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DOI：
10.1194/jlr.m900083-jlr200
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发表时间：
2010-04
影响因子：
6.5
通讯作者：
Soonkyu Chung;A. Gebre;Jeongmin Seo;G. S. Shelness;J. Parks
中科院分区：
文献类型：
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作者：
Soonkyu Chung;A. Gebre;Jeongmin Seo;G. S. Shelness;J. Parks
在丹吉尔病中，ATP结合盒转运蛋白A1（ABCA 1）的缺失导致血浆HDL降低和甘油三酯（TG）水平升高。我们假设肝细胞ABCA 1通过新生HDL的产生调节VLDL TG的分泌。油酸刺激的大鼠肝癌细胞中ABCA 1表达的沉默导致：1）减少大的新生HDL（直径>10 nm）和增加小的新生HDL（<10 nm）形成，2）增加大的漂浮VLDL 1颗粒分泌，和3）减少磷脂酰肌醇-3（PI 3）激酶激活。新生HDL的条件培养基从大鼠肝癌细胞或HEK 293细胞转染ABCA 1是有效的，在增加PI 3激酶激活和减少VLDL TG分泌ABCA 1沉默肝癌细胞。此外，孤立的大新生HDL颗粒ABCA 1沉默肝癌细胞抑制VLDL TG分泌的程度比小新生HDL。类似地，在ABCA 1沉默的细胞中，添加重组HDL而不是人血浆HDL在减弱TG分泌和增加PI 3激酶活化方面是有效的。总的来说，这些数据表明，大的新生HDL颗粒，由肝脏ABCA 1组装，产生PI 3激酶介导的自分泌信号，减弱VLDL成熟和TG分泌。这种途径可以解释大多数丹吉尔受试者血浆TG浓度升高的原因，也可以部分解释ABCA 1功能受损个体血浆HDL和TG浓度之间的反比关系。
In Tangier disease, absence of ATP binding cassette transporter A1 (ABCA1) results in reduced plasma HDL and elevated triglyceride (TG) levels. We hypothesized that hepatocyte ABCA1 regulates VLDL TG secretion through nascent HDL production. Silencing of ABCA1 expression in oleate-stimulated rat hepatoma cells resulted in: 1) decreased large nascent HDL (>10 nm diameter) and increased small nascent HDL (<10 nm) formation, 2) increased large buoyant VLDL1 particle secretion, and 3) decreased phosphatidylinositol-3 (PI3) kinase activation. Nascent HDL-containing conditioned medium from rat hepatoma cells or HEK293 cells transfected with ABCA1 was effective in increasing PI3 kinase activation and reducing VLDL TG secretion in ABCA1-silenced hepatoma cells. Addition of isolated large nascent HDL particles to ABCA1-silenced hepatoma cells inhibited VLDL TG secretion to a greater extent than small nascent HDL. Similarly, addition of recombinant HDL, but not human plasma HDL, was effective in attenuating TG secretion and increasing PI3 kinase activation in ABCA1-silenced cells. Collectively, these data suggest that large nascent HDL particles, assembled by hepatic ABCA1, generate a PI3 kinase-mediated autocrine signal that attenuates VLDL maturation and TG secretion. This pathway may explain the elevated plasma TG concentration that occurs in most Tangier subjects and may also account, in part, for the inverse relationship between plasma HDL and TG concentrations in individuals with compromised ABCA1 function.