Institute for Clinical Chemistry, University and University Hospital Zurich, Zurich, Switzerland; Centre for Integrative Human Physiology, University of Zurich, Zurich, Switzerland.
Institute for Clinical Chemistry, University and University Hospital Zurich, Zurich, Switzerland; Centre for Integrative Human Physiology, University of Zurich, Zurich, Switzerland.
Atherosclerosis. 2018 Aug;275:273-295. doi: 10.1016/j.atherosclerosis.2018.06.881. Epub 2018 Jun 23.
During their metabolism, all lipoproteins undergo endocytosis, either to be degraded intracellularly, for example in hepatocytes or macrophages, or to be re-secreted, for example in the course of transcytosis by endothelial cells. Moreover, there are several examples of internalized lipoproteins sequestered intracellularly, possibly to exert intracellular functions, for example the cytolysis of trypanosoma. Endocytosis and the subsequent intracellular itinerary of lipoproteins hence are key areas for understanding the regulation of plasma lipid levels as well as the biological functions of lipoproteins. Indeed, the identification of the low-density lipoprotein (LDL)-receptor and the unraveling of its transcriptional regulation led to the elucidation of familial hypercholesterolemia as well as to the development of statins, the most successful therapeutics for lowering of cholesterol levels and risk of atherosclerotic cardiovascular diseases. Novel limiting factors of intracellular trafficking of LDL and the LDL receptor continue to be discovered and to provide drug targets such as PCSK9. Surprisingly, the receptors mediating endocytosis of high-density lipoproteins or lipoprotein(a) are still a matter of controversy or even new discovery. Finally, the receptors and mechanisms, which mediate the uptake of lipoproteins into non-degrading intracellular itineraries for re-secretion (transcytosis, retroendocytosis), storage, or execution of intracellular functions, are largely unknown.
在代谢过程中，所有脂蛋白都经历内吞作用，要么在肝细胞或巨噬细胞中被降解，要么被重新分泌，例如在内皮细胞的转胞吞作用过程中。此外，还有一些被内吞并在细胞内隔离的脂蛋白的例子，可能发挥细胞内功能，例如锥虫的细胞溶解。因此，内吞作用和脂蛋白的随后的细胞内途径是理解血浆脂质水平的调节以及脂蛋白的生物学功能的关键领域。事实上，低密度脂蛋白（LDL）受体的鉴定及其转录调控的阐明导致了家族性高胆固醇血症的阐明，以及他汀类药物的发展，他汀类药物是降低胆固醇水平和动脉粥样硬化性心血管疾病风险的最成功的治疗方法。新发现的 LDL 和 LDL 受体的细胞内运输的限制因素继续被发现，并提供了药物靶点，如 PCSK9。令人惊讶的是，介导高密度脂蛋白或脂蛋白（a）内吞作用的受体仍然存在争议，甚至是新的发现。最后，介导脂蛋白进入非降解的细胞内途径进行重新分泌（转胞吞作用、逆行内吞作用）、储存或执行细胞内功能的受体和机制在很大程度上是未知的。
