Human hormone-sensitive lipase (HSL):: expression in white fat corrects the white adipose phenotype of HSL-deficient mice
Human hormone-sensitive lipase (HSL):: expression in white fat corrects the white adipose phenotype of HSL-deficient mice
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DOI：
10.1194/jlr.m500081-jlr200
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发表时间：
2005-09-01
影响因子：
6.5
通讯作者：
Mitchell, GA
中科院分区：
文献类型：
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作者：
Fortier, M;Soni, K;Mitchell, GA
在白色脂肪组织(WAT)中，激素敏感脂肪酶(HSL)可以介导脂肪分解，这是肥胖和糖尿病的中心途径。没有检测到HSL多肽或活性(以胆固醇酯酶衡量)的基因靶向HSL缺陷(HSL-/-)小鼠有Wat异常，包括低质量、显著的细胞直径不均一、二酰甘油含量增加以及脂肪细胞脂肪分解的低β-肾上腺素能刺激。在WAT中优先表达人HSL的三个转基因小鼠品系被培育成HSL-/-背景。一个是HSL-/-N，表达正常人类HSL(41.3+/-9.1%的正常活性)；两个表达一个丝氨酸-丙氨酸突变(S554A)，最初被认为是组成活性的：HSL-/-ML，50.3+/-12.3%正常，HSL-/-MH，69.8+/-15.8%。在WAT中，HSL-/-N小鼠在Wat质量、组织学、二酰甘油酯含量和对β-肾上腺素能药物的脂解反应方面与HSL(-/-)对照组相似。相反，HSL-/-ML和HSL-/-MH小鼠与非转基因HS(-/-)小鼠相似，只是HSL-/-MH小鼠的二酰甘油含量以及肾周和腹股沟Wat质量接近正常。因此，1)正常人HSL的WAT表达显著改善了HSL(-/-)WAT的生化、生理和形态；2)相似水平的S554A HSL在体外具有较低的生理效应；以及3)二酰甘油的积累对于HSL(-/-)小鼠特有的Wat病理的发生并不是必需的。
In white adipose tissue (WAT), hormone-sensitive lipase (HSL) can mediate lipolysis, a central pathway in obesity and diabetes. Gene-targeted HSL-deficient (HSL-/-) mice with no detectable HSL peptide or activity (measured as cholesteryl esterase) have WAT abnormalities, including low mass, marked heterogeneity of cell diameter, increased diacylglycerol content, and low beta-adrenergic stimulation of adipocyte lipolysis. Three transgenic mouse strains preferentially expressing human HSL in WAT were bred to a HSL-/- background. One, HSL-/-N, expresses normal human HSL (41.3 +/- 9.1% of normal activity); two express a serine-to-alanine mutant (S554A) initially hypothesized to be constitutively active: HSL-/-ML, 50.3 +/- 12.3% of normal, and HSL-/-MH, 69.8 +/- 15.8% of normal. In WAT, HSL-/-N mice resembled HSL(-/-)controls in WAT mass, histology, diacylglyceride content, and lipolytic response to beta - adrenergic agents. In contrast, HSL-/-ML and HSL-/-MH mice resembled nontransgenic HS(-/-)mice, except that diacylglycerol content and perirenal and inguinal WAT masses approached normal in HSL-/-MH mice. Therefore, 1) WAT expression of normal human HSL markedly improves HSL(-/-)WAT biochemically, physiologically, and morphologically; 2) similar levels of S554A HSL have a low physiological effect despite being active in vitro; and 3) diacylglycerol accumulation is not essential for the development of the characteristic WAT pathology of HSL(-/-)mice.