Targeted disruption of the mouse lysosomal acid lipase gene: long-term survival with massive cholesteryl ester and triglyceride storage
Targeted disruption of the mouse lysosomal acid lipase gene: long-term survival with massive cholesteryl ester and triglyceride storage
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DOI：
10.1093/hmg/7.9.1347
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发表时间：
1998-09-01
影响因子：
3.5
通讯作者：
Grabowski, GA
中科院分区：
文献类型：
--
作者：
Du, H;Duanmu, M;Grabowski, GA
溶酶体酸性脂肪酶 (LAL) 对于溶酶体中甘油三酯和胆固醇酯的水解至关重要。它的缺乏会产生两种表型，一种是严重的婴儿发病变异，即沃尔曼病 (WD)，另一种是晚发型变异，即胆固醇酯贮积病 (CESD)。通过靶向破坏小鼠基因，产生了具有 LAL 无效突变的小鼠模型。纯合基因敲除小鼠 (lal(-)/lal(-)) 不产生 LAL mRNA、蛋白质或酶活性。 lal(-)/lal(-) 小鼠以孟德尔比例出生，出生时外观正常，并遵循正常发育至成年期。然而，甘油三酯和胆固醇酯在多个器官中大量积累，到21天时，肝脏呈现黄橙色，比正常值大1.5-2.0倍，积累的胆固醇酯和甘油三酯比正常值大30倍。 lal(+)/lal(-)小鼠具有与正常LAL活性相似的50%并且没有显示脂质积累。雄性和雌性 lal(-)/lal(-) 小鼠具有生育能力，可以繁殖产生后代。该小鼠模型是人类 CESD 的表型模型，也是人类 WD 的生化和组织病理学模拟。lal(-)/lal(-) 小鼠提供了一个模型来确定 LAL 在脂质代谢中的作用及其缺乏状态的发病机制。
Lysosomal acid lipase (LAL) is essential for the hydrolysis of the triglycerides and cholesteryl esters in lysosomes, Its deficiency produces two phenotypes, a severe infantile-onset variant, Wolman disease (WD), and a later onset variant, cholesteryl ester storage disease (CESD), A mouse model with a LAL null mutation was produced by targeting disruption of the mouse gene. Homozygote knockout mice (lal(-)/lal(-)) produce no LAL mRNA, protein or enzyme activity, The lal(-)/lal(-) mice are born in Mendelian ratios, are normal appearing at birth, and follow normal development into adulthood. However, massive accumulation of triglycerides and cholesteryl esters occurs in several organs, By 21 days, the liver develops a yellow-orange color and is similar to 1.5-2.0x larger than normal, The accumulated cholesteryl esters and triglycerides are similar to 30-fold greater than normal. The lal(+)/lal(-) mice have similar to 50% of normal LAL activity and do not show lipid accumulation. Male and female lal(-)/lal(-) mice are fertile and can be bred to produce progeny, This mouse model is a phenotypic model of human CESD, and a biochemical and histopathologic mimic of human WD, The lal(-)/lal(-) mice provide a model to determine the role of LAL in lipid metabolism and the pathogenesis of its deficiency states.