Laatsch Alexander, Merkel Martin, Talmud Philippa J, Grewal Thomas, Beisiegel Ulrike, Heeren Joerg
Department of Biochemistry and Molecular Biology II: Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Atherosclerosis. 2009 May;204(1):105-11. doi: 10.1016/j.atherosclerosis.2008.07.046. Epub 2008 Aug 29.
While the role of insulin in glucose uptake and its aberration in diabetes are well established, the effect of insulin on lipoprotein clearance in the postprandial phase is not yet fully understood. The dietary lipids are carried in chylomicron remnants (CR) which are taken up into the liver mainly via LDLR-related protein 1 (LRP1). In this study, the effect of insulin on LRP1-mediated hepatic CR uptake was investigated.
The study was based on determining the subcellular localisation of LRP1 by subcellular fractionation and immunofluorescence microscopy and correlating those findings with the hepatic uptake of fluorescently or radioactively labelled LRP1-specific ligands and CR in hepatoma cells, primary hepatocytes and mouse models.
In vitro and in vivo, insulin stimulated the translocation of hepatic LRP1 from intracellular vesicles to the plasma membrane, which correlates with an increased uptake of LRP1-specific ligands. In wild-type mice, a glucose-induced insulin response increased the hepatic uptake of LRP1 ligands while in leptin-deficient obese mice (ob/ob), which are characterised by hepatic insulin resistance, insulin-inducible LRP1 ligand uptake was abolished. Finally, upon hepatic LRP1 knockdown, insulin no longer significantly enhanced CR uptake into the liver. The insulin-induced LRP1-mediated CR uptake, as demonstrated here, suggests that impaired hepatic LRP1 translocation can contribute to the postprandial lipaemia in insulin resistance.
虽然胰岛素在葡萄糖摄取中的作用及其在糖尿病中的异常已得到充分证实，但胰岛素在餐后阶段对脂蛋白清除的影响尚未完全了解。膳食脂质存在于乳糜微粒残粒（CR）中，这些残粒主要通过低密度脂蛋白受体相关蛋白1（LRP1）被肝脏摄取。在本研究中，研究了胰岛素对LRP1介导的肝脏CR摄取的影响。
该研究基于通过亚细胞分级分离和免疫荧光显微镜确定LRP1的亚细胞定位，并将这些结果与肝癌细胞、原代肝细胞和小鼠模型中荧光或放射性标记的LRP1特异性配体和CR的肝脏摄取相关联。
在体外和体内，胰岛素刺激肝脏LRP1从细胞内囊泡向质膜的转运，这与LRP1特异性配体摄取增加相关。在野生型小鼠中，葡萄糖诱导的胰岛素反应增加了肝脏对LRP1配体的摄取，而在以肝脏胰岛素抵抗为特征的瘦素缺乏肥胖小鼠（ob/ob）中，胰岛素诱导的LRP1配体摄取被消除。最后，在肝脏LRP1基因敲低后，胰岛素不再显著增强CR向肝脏的摄取。此处所示的胰岛素诱导的LRP1介导的CR摄取表明，肝脏LRP1转运受损可能导致胰岛素抵抗中的餐后血脂异常。
