Impaired receptor-mediated catabolism of low density lipoprotein in the WHHL rabbit, an animal model of familial hypercholesterolemia.
Impaired receptor-mediated catabolism of low density lipoprotein in the WHHL rabbit, an animal model of familial hypercholesterolemia.
复制标题
WHHL 兔（家族性高胆固醇血症动物模型）中受体介导的低密度脂蛋白分解代谢受损。
DOI：
10.1073/pnas.79.10.3305
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发表时间：
1982
影响因子：
11.1
通讯作者：
Kita,T
中科院分区：
文献类型：
--
作者：
Bilheimer,DW;Watanabe,Y;Kita,T
纯合 WHHL（渡边遗传性高脂血症）兔在培养的成纤维细胞和肝膜上不显示或仅显示最低限度的低密度脂蛋白 (LDL) 受体活性，因此已被提议作为人类家族性高胆固醇血症的动物模型。为了评估这种突变对体内 LDL 代谢的影响，我们使用天然兔 LDL 和不与 LDL 受体结合的化学修饰 LDL（即甲基 LDL），在正常和 WHHL 兔子中进行了脂蛋白周转研究。正常兔子的 LDL 总分解代谢率 (FCR) 是 WHHL 兔子的 3.5 倍。正常兔子中 LDL 总 FCR 的 67% 归因于 LDL 受体介导的清除，33% 归因于不依赖于受体的过程；在 WHHL 兔子中，基本上所有 LDL 都是通过不依赖受体的过程分解代谢的。尽管与正常兔子相比，WHHL 中 LDL 脱辅基蛋白 (apo-LDL) 的血浆库大小增加了 17.5 倍，但两种品系中受体独立的 FCR（根据甲基 LDL 的周转来判断）相似。因此，不依赖于受体的分解代谢过程不受影响 LDL 受体的突变的影响。 WHHL 兔子的 apo-LDL 合成和分解代谢的绝对速率也增加了 5.6 倍。从绝对值来看，WHHL 兔子通过受体非依赖性途径清除的 apo-LDL 比正常兔子多 19 倍，而通过受体依赖性途径几乎没有清除。这些结果表明纯合 WHHL 兔与人类家族性高胆固醇血症具有许多共同的代谢特征，并且应该作为研究与受体异常相关的脂蛋白代谢改变的有用模型。我们还注意到，正常兔体内人和兔 LDL 的体内代谢行为不同，人 LDL 的平均总 FCR 仅为兔 LDL 平均总 FCR 的 64%，而人和兔甲基 LDL 的清除率相同。因此，如果在这些研究中使用人类 LDL 和甲基 LDL，则总 FCR 和受体依赖性 FCR 的大小都会被低估。
The homozygous WHHL (Watanabe heritable hyperlipidemic) rabbit displays either no or only minimal low density lipoprotein (LDL) receptor activity on cultured fibroblasts and liver membranes and has therefore been proposed as an animal model for human familial hypercholesterolemia. To assess the impact of this mutation on LDL metabolismin vivo, we performed lipoprotein turnover studies in normal and WHHL rabbits using both native rabbit LDL and chemically modified LDL (i.e., methyl-LDL) that does not bind to LDL receptors. The total fractional catabolic rate (FCR) for LDL in the normal rabbit was 3.5-fold greater than in the WHHL rabbit. Sixty-seven percent of the total FCR for LDL in the normal rabbit was due to LDL receptor-mediated clearance and 33% was attributable to receptor-independent processes; in the WHHL rabbit, essentially all of the LDL was catabolized via receptor-independent processes. Despite a 17.5-fold elevated plasma pool size of LDL apoprotein (apo-LDL) in WHHL as compared to normal rabbits, the receptor-independent FCR—as judged by the turnover of methyl-LDL—was similar in the two strains. Thus, the receptor-independent catabolic processes are not influenced by the mutation affecting the LDL receptor. The WHHL rabbits also exhibited a 5.6-fold increase in the absolute rate of apo-LDL synthesis and catabolism. In absolute terms, the WHHL rabbit cleared 19-fold more apo-LDL via receptor-independent processes than did the normal rabbit and cleared virtually none by the receptor-dependent pathway. These results indicate that the homozygous WHHL rabbit shares a number of metabolic features in common with human familial hypercholesterolemia and should serve as a useful model for the study of altered lipoprotein metabolism associated with receptor abnormalities. We also noted that thein vivometabolic behavior of human and rabbit LDL in the normal rabbit differed such that the mean total FCR for human LDL was only 64% of the mean total FCR for rabbit LDL, whereas human and rabbit methyl-LDL were cleared at identical rates. Thus, if human LDL and methyl-LDL had been used in these studies, the magnitude of both the total and receptor-dependent FCR would have been underestimated.