Altered structure of LDL receptor and cholesterol metabolic defects.

高胆固醇血症和动脉粥样硬化似乎是高血压的主要起源。我们已经建立了两个系统的模型细胞系在培养改变胆固醇代谢疾病和动脉粥样硬化泡沫细胞。第一个系统是建立和鉴定具有固醇代谢调节缺陷的体细胞突变体。我们选择了具有非常高固醇合成的动物细胞突变体，它们携带糖链改变的低密度脂蛋白（LDL）受体。这些突变体应该会影响高尔基体的功能。这个新基因int的发现可能意味着高胆固醇血症的进一步病因。二是利用已建立的小鼠巨噬细胞J774细胞系进行培养，研究动脉粥样硬化泡沫细胞的形成机制。当天然LDL受到挑战时，J774细胞会装载胆固醇酯。对J774细胞LDL受体的生物合成、加工和降解的分析表明，与其他非巨噬细胞系相比，J774细胞的LDL受体降解速度非常快。该巨噬细胞系模型系统可能为天然LDL参与早期动脉粥样硬化变化提供了除变性LDL清道夫通路模型外的新思路。

Hypercholesterolemia and atherosclerosis are plausibly main origins for hypertension. We have established two systems of model cell lines in culture for altered cholesterol metabolic disease and also atheromatous foam cells.First system is to establish and characterize somatic cell mutants with defects in the regulation of sterol metabolism. We have selected animal cell mutants with very high sterol synthesis, and they carry low density lipoprotein (LDL) receptors with altered sugar chains. These mutants are supposed to affect Golgi apparatus function. discovery of this new gene, int, may imply a further etiology for hypercholesterolemia.Second system is to study mechanism for appearance of atheromatous foam cells by using established mouse macrophage J774 cell line in culture. J774 cells are loaded with cholesterol esters when native LDL is challenged. Analysis of biosynthesis, processing and degradation of LDL receptors of J774 cells shows very rapid rate of degradation of LDL receptors in comparison with other non-macrophage cell lines. This model system with macrophage cell line might imply new idea for involvement of native LDL in earlier atherosclerosis change besides scavenger pathway model with denatured LDL.