Hormone-sensitive lipase deficiency in mice causes diglyceride accumulation in adipose tissue, muscle, and testis
Hormone-sensitive lipase deficiency in mice causes diglyceride accumulation in adipose tissue, muscle, and testis
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DOI：
10.1074/jbc.m110355200
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发表时间：
2002-02-15
影响因子：
4.8
通讯作者：
Zechner, R
中科院分区：
文献类型：
--
作者：
Haemmerle, G;Zimmermann, R;Zechner, R
激素敏感性脂肪酶（HSL）主要在白色和棕色脂肪组织中表达，据信其在储存的甘油三酯（TG）的脂解中起关键作用，从而以游离脂肪酸（FFA）的形式为身体提供能量底物。从体外测定中，已知HSL水解TG、甘油二酯（DG）、胆固醇酯和视黄酯。在目前的研究中，我们已经产生了HSL基因敲除小鼠，并证明了三条线的证据表明，HSL是有助于在体内DG的catastrophic。首先，小鼠HSL缺乏导致DG在白色脂肪组织、棕色脂肪组织、骨骼肌、心肌和睾丸中积累。第二，当组织提取物用于体外脂肪酶测定时，在HSL敲除小鼠中观察到FFA释放减少和DG积累，而当使用对照小鼠的组织提取物时未发生这种情况。第三，在体外脂肪分解实验与HSL缺陷脂肪垫表明，异丙肾上腺素刺激的FFA释放减少和DG积累细胞内导致在基本上没有异丙肾上腺素刺激的甘油形成通常观察到的控制脂肪垫。此外，在白色脂肪组织中不存在HSL导致TG部分的脂肪酸组成向增加的长链脂肪酸转变，这意味着酶在体内的底物特异性。从这些在体内的结果，我们得出结论，HSL是限速酶的DG在脂肪组织和肌肉中的细胞catalysts。
Hormone-sensitive lipase (HSL) is expressed predominantly in white and brown adipose tissue where it is believed to play a crucial role in the lipolysis of stored triglycerides (TG), thereby providing the body with energy substrate in the form of free fatty acids (FFA). From in vitro assays, HSL is known to hydrolyze TG, diglycerides (DG), cholesteryl esters, and retinyl esters. In the current study we have generated HSL knock-out mice and demonstrate three lines of evidence that HSL is instrumental in the catabolism of DG in vivo. First, HSL deficiency in mice causes the accumulation of DG in white adipose tissue, brown adipose tissue, skeletal muscle, cardiac muscle, and testis. Second, when tissue extracts were used in an in vitro lipase assay, a reduced FFA release and the accumulation of DG was observed in HSL knock-out mice which did not occur when tissue extracts from control mice were used. Third, in vitro lipolysis experiments with HSL-deficient fat pads demonstrated that the isoproterenol-stimulated release of FFA was decreased and DG accumulated intracellularly resulting in the essential absence of the isoproterenol-stimulated glycerol formation typically observed in control fat pads. Additionally, the absence of HSL in white adipose tissue caused a shift of the fatty acid composition of the TG moiety toward increased long chain fatty acids implying a substrate specificity of the enzyme in vivo. From these in vivo results we conclude that HSL is the rate-limiting enzyme for the cellular catabolism of DG in adipose tissue and muscle.