Post-transcriptional regulation of low density lipoprotein receptor protein by proprotein convertase subtilisin/kexin type 9a in mouse liver
Post-transcriptional regulation of low density lipoprotein receptor protein by proprotein convertase subtilisin/kexin type 9a in mouse liver
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DOI：
10.1074/jbc.m410077200
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发表时间：
2004-11-26
影响因子：
4.8
通讯作者：
Horton, JD
中科院分区：
文献类型：
--
作者：
Park, SW;Moon, YA;Horton, JD
脂质体内平衡由三种DNA结合蛋白（命名为固醇调节元件结合蛋白（SREBP）-1a、-1c和-2）进行转录调节。最近，与转基因SREBP-1a、转基因SREBP-2和SREBP切割激活蛋白敲除小鼠肝脏RNA杂交的寡核苷酸阵列鉴定了肝脏中受SREBP调控的33个基因，其中4个与脂质代谢无关。四个基因之一是PCSK 9，其编码前蛋白转化酶枯草杆菌蛋白酶/kexin 9a型，一种属于枯草杆菌酶的蛋白酶K亚家族的蛋白质。PCSK 9突变与常染色体显性形式的高胆固醇血症相关。在这里，我们证明了野生型或突变型PCSK 9在小鼠中的肝脏过表达导致高胆固醇血症。高胆固醇血症是由于转录后事件导致低密度脂蛋白（LDL）受体蛋白在受体内化和再循环之前减少。原代肝细胞和缺乏LDL受体的小鼠中PCSK 9的过表达不会改变载脂蛋白B的分泌。这些数据与PCSK 9通过转录后机制改变LDL受体蛋白水平影响血浆LDL胆固醇水平一致。
Lipid homeostasis is transcriptionally regulated by three DNA-binding proteins, designated sterol regulatory element-binding protein (SREBP)-1a, - 1c, and -2. Oligonucleotide arrays hybridized with RNA made from livers of transgenic SREBP-1a, transgenic SREBP-2, and SREBP cleavage-activating protein knockout mice recently identified 33 genes regulated by SREBPs in liver, four of which had no known connection to lipid metabolism. One of the four genes was PCSK9, which encodes proprotein convertase subtilisin/kexin type 9a, a protein that belongs to the proteinase K subfamily of subtilases. Mutations in PCSK9 are associated with an autosomal dominant form of hypercholesterolemia. Here, we demonstrate that hepatic overexpression of either wild-type or mutant PCSK9 in mice results in hypercholesterolemia. The hypercholesterolemia is due to a post-transcriptional event causing a reduction in low density lipoprotein (LDL) receptor protein prior to the internalization and recycling of the receptor. Overexpression of PCSK9 in primary hepatocytes and in mice lacking the LDL receptor does not alter apolipoprotein B secretion. These data are consistent with PCSK9 affecting plasma LDL cholesterol levels by altering LDL receptor protein levels via a post-transcriptional mechanism.