Targeted disruption of hormone-sensitive lipase results in male sterility and adipocyte hypertrophy, but not in obesity
Targeted disruption of hormone-sensitive lipase results in male sterility and adipocyte hypertrophy, but not in obesity
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DOI：
10.1073/pnas.97.2.787
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发表时间：
2000-01-18
影响因子：
11.1
通讯作者：
Yamada, N
中科院分区：
文献类型：
--
作者：
Osuga, J;Ishibashi, S;Yamada, N
激素敏感脂肪酶(HSL)不仅能降解储存在脂肪组织中的三酰甘油，还能降解肾上腺、卵巢、睾丸和巨噬细胞中的胆固醇酯。为了阐明它在肥胖和类固醇生成中的确切作用，我们通过胚胎干细胞中的同源重组产生了HSL基因敲除小鼠。突变的HSL等位基因(HSL-/-)纯合子的小鼠表面上是正常的，除了雄性小鼠因为少精子症而不育。HSL-/-小鼠没有性腺功能减退或肾上腺功能不全。相反，睾丸完全缺乏中性胆固醇酯水解酶(NCEH)活性，并含有大量的胆固醇酯。生精小管内可见大量上皮细胞空泡化。在HSL-/-小鼠中，棕色脂肪组织(BAT)和白色脂肪组织(WAT)中完全没有NCEH活性。一致地，脂肪细胞在蝙蝠中显著扩大(5倍)，在WAT中程度较小(2倍)，支持三酰甘油的水解至少部分地在HSL-/-小鼠中受损的概念。蝙蝠的质量增加了1.65倍，但Wat的质量保持不变。细胞和组织的大小差异表明脂肪细胞的异质性。尽管有这些形态变化，HSL-/-小鼠既不肥胖，也不冷敏感。此外，与野生型Wat相比，来自HSL-/-小鼠的Wat保留了40%的三酰甘油脂肪酶活性。总而言之，HSL是精子发生所必需的，但并不是唯一一种介导储存在脂肪细胞中的三酰甘油水解酶。
Hormone-sensitive lipase (HSL) is known to mediate the hydrolysis not only of triacylglycerol stored in adipose tissue but also of cholesterol esters in the adrenals, ovaries, testes, and macrophages. To elucidate its precise role in the development of obesity and steroidogenesis, we generated HSL knockout mice by homologous recombination in embryonic stem cells. Mice homozygous for the mutant HSL allele (HSL- / -) were superficially normal except that the males were sterile because of oligospermia. HSL- / - mice did not have hypogonadism or adrenal insufficiency. Instead, the testes completely lacked neutral cholesterol ester hydrolase (NCEH) activities and contained increased amounts of cholesterol ester. Many epithelial cells in the seminiferous tubules were vacuolated. NCEH activities were completely absent from both brown adipose tissue (BAT) and white adipose tissue (WAT) in HSL- / - mice. Consistently, adipocytes were significantly enlarged in the BAT (5-fold) and, to a lesser extent in the WAT (2-fold), supporting the concept that the hydrolysis of triacylglycerol was, at least in part, impaired in HSL- / - mice. The BAT mass was increased by 1.65-fold, but the WAT mass remained unchanged. Discrepancy of the size differences between cell and tissue suggests the heterogeneity of adipocytes. Despite these morphological changes, HSL- / - mice were neither obese nor cold sensitive. Furthermore, WAT from HSL- / - mice retained 40% of triacylglycerol lipase activities compared with the wild-type WAT. In conclusion, HSL is required for spermatogenesis but is not the only enzyme that mediates the hydrolysis of triacylglycerol stored in adipocytes.