THE 2-RECEPTOR MODEL OF LIPOPROTEIN CLEARANCE - TESTS OF THE HYPOTHESIS IN KNOCKOUT MICE LACKING THE LOW-DENSITY-LIPOPROTEIN RECEPTOR, APOLIPOPROTEIN-E, OR BOTH PROTEINS
THE 2-RECEPTOR MODEL OF LIPOPROTEIN CLEARANCE - TESTS OF THE HYPOTHESIS IN KNOCKOUT MICE LACKING THE LOW-DENSITY-LIPOPROTEIN RECEPTOR, APOLIPOPROTEIN-E, OR BOTH PROTEINS
复制标题
DOI：
10.1073/pnas.91.10.4431
复制
发表时间：
1994-05-10
影响因子：
11.1
通讯作者：
BROWN, MS
中科院分区：
文献类型：
--
作者：
ISHIBASHI, S;HERZ, J;BROWN, MS
假设载脂蛋白 E (apoE) 通过与两种受体结合来介导脂蛋白清除：(i) 低密度脂蛋白受体 (LDLR) 和 (ii) 乳糜微粒残余受体。为了检验这一假设，我们比较了纯合小鼠的血浆脂蛋白，以靶向破坏 apoE [apoE(-/-)]、LDLR [LDLR(-/-)] 和两种分子 [apoE(-/-); LDLR(-/-)]。在正常饮食下，apoE(-/-) 小鼠的平均血浆胆固醇水平高于 LDLR(-/-) 小鼠（579 mg/dl vs. 268 mg/dl）。 apoE (-/-) 中的胆固醇水平； LDLR(-/-)小鼠与apoE(-/-)小鼠没有显着差异。 LDLR(-/-)小鼠的血浆LDL水平相对孤立地升高，而apoE(-/-)小鼠的较大脂蛋白(对应于极低密度脂蛋白和乳糜微粒残余物)显着增加。 apoE(-/-) 中的脂蛋白模式； LDLR(-/-)小鼠与apoE(-/-)小鼠相似。 LDLR(-/-)小鼠的apoB-100显着升高，apoB-48适度升高。相比之下，apoE(-/-) 小鼠的 apoB-48 显着升高，但 apoB-100 没有显着升高。 LDLR(-/-)； apoE(-/-) 双纯合子的两种载脂蛋白均显着升高。 apoB-48 在 apoE 缺陷时比在 LDLR 缺陷时增加更显着，这一观察结果支持了 apoE 与除 LDLR 之外的第二种受体结合的观点。 LDLR 缺陷与 apoE 缺陷叠加的观察结果也支持了这一结论 [apoE(-/-); LDLR(-/-)双纯合子]不会增加高胆固醇血症超过单独apoE缺陷观察到的水平。
Apolipoprotein E (apoE) is hypothesized to mediate lipoprotein clearance by binding to two receptors: (i) the low density lipoprotein receptor (LDLR) and (ii) a chylomicron remnant receptor. To test this hypothesis, we have compared plasma lipoproteins in mice that are homozygous for targeted disruptions of the genes for apoE [apoE(-/-)], the LDLR [LDLR(-/-)], and both molecules [apoE(-/-); LDLR(-/-)]. On a normal chow diet, apoE(-/-) mice had higher mean plasma cholesterol levels than LDLR(-/-) mice (579 vs. 268 mg/dl). Cholesterol levels in the apoE(-/-); LDLR(-/-) mice were not significantly different from those in the apoE(-/-) mice. LDLR(-/-) mice had a relatively isolated elevation in plasma LDL, whereas apoE(-/-) mice had a marked increase in larger lipoproteins corresponding to very low density lipoproteins and chylomicron remnants. The lipoprotein pattern in apoE(-/-); LDLR(-/-) mice resembled that of apoE(-/-) mice. The LDLR(-/-) mice had a marked elevation in apoB-100 and a modest increase in apoB-48. In contrast, the apoE(-/-) mice had a marked elevation in apoB-48 but not in apoB-100. The LDLR(-/-); apoE(-/-) double homozygotes had marked elevations of both apolipoproteins. The observation that apoB-48 increases more dramatically with apoE deficiency than with LDLR deficiency supports the notion that apoE binds to a second receptor in addition to the LDLR. This conclusion is also supported by the observation that superimposition of a LDLR deficiency onto an apoE deficiency [apoE(-/-); LDLR(-/-) double homozygotes] does not increase hypercholesterolemia beyond the level observed with apoE deficiency alone.