Tao Wensi, Moore Robert, Meng Yue, Smith Elizabeth R, Xu Xiang-Xi
Department of Cell Biology, Molecular Cell and Developmental Biology Graduate Program, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136.
Department of Cell Biology, Molecular Cell and Developmental Biology Graduate Program, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136
J Lipid Res. 2016 May;57(5):809-17. doi: 10.1194/jlr.M063065. Epub 2016 Mar 22.
High serum cholesterol (hypercholesterolemia) strongly associates with cardiovascular diseases as the atherogenic LDLs promote atheroma development in arteries (atherosclerosis). LDL clearance from the circulation by LDL receptor (LDLR)-mediated endocytosis by hepatic and peripheral tissues and subsequent feedback regulation of endogenous synthesis of cholesterol is a key determinant of serum LDL level. Human mutation analysis revealed that autosomal recessive hypercholesterolemia (ARH), an LDLR endocytic adaptor, perturbs LDLR function and thus impacts serum cholesterol levels. In our genetic analysis of mutant mice, we found that deletion of another LDLR endocytic adaptor, Disabled-2 (Dab2), only slightly affected serum cholesterol levels. However, elimination of both arh and dab2 genes in mice resulted in profound hypercholesterolemia similar to that resulting from ldlr homozygous deletion. In the liver, Dab2 is expressed in sinusoid endothelial cells but not in hepatocytes. When deleting both Dab2 and Arh, HMG-CoA reductase level increased to the level similar to that of ldlr knockout. Thus, in the absence of Arh, Dab2 in liver endothelial cells regulates cholesterol synthesis in hepatocytes. We conclude that the combination of Arh and Dab2 is responsible for the majority of adaptor function in LDLR endocytosis and LDLR-mediated cholesterol homeostasis.
高血清胆固醇（高胆固醇血症）与心血管疾病密切相关，因为致动脉粥样硬化的低密度脂蛋白（LDL）会促进动脉粥样硬化斑块的形成（动脉粥样硬化）。肝脏和外周组织通过LDL受体（LDLR）介导的内吞作用从循环中清除LDL，以及随后对胆固醇内源性合成的反馈调节是血清LDL水平的关键决定因素。人类突变分析表明，常染色体隐性高胆固醇血症（ARH），一种LDLR内吞衔接蛋白，会扰乱LDLR功能，从而影响血清胆固醇水平。在我们对突变小鼠的基因分析中，我们发现另一种LDLR内吞衔接蛋白Disabled-2（Dab2）的缺失仅对血清胆固醇水平有轻微影响。然而，在小鼠中同时敲除arh和dab2基因会导致严重的高胆固醇血症，类似于ldlr纯合缺失所导致的情况。在肝脏中，Dab2在肝窦内皮细胞中表达，但在肝细胞中不表达。当同时敲除Dab2和Arh时，HMG-CoA还原酶水平升高到与ldlr基因敲除小鼠相似的水平。因此，在没有Arh的情况下，肝脏内皮细胞中的Dab2调节肝细胞中的胆固醇合成。我们得出结论，Arh和Dab2的组合在LDLR内吞作用和LDLR介导的胆固醇稳态中负责大部分衔接蛋白功能。
