Targeted disruption of hormone-sensitive lipase results in male sterility and adipocyte hypertrophy, but not in obesity

被引:486
作者
Osuga, J
Ishibashi, S [1 ]
Oka, T
Yagyu, H
Tozawa, R
Fujimoto, A
Shionoiri, F
Yahagi, N
Kraemer, FB
Tsutsumi, O
Yamada, N
机构
[1] Univ Tokyo, Fac Med, Dept Metab Dis, Tokyo 113, Japan
[2] Univ Tokyo, Fac Med, Dept Pathol, Tokyo 113, Japan
[3] Univ Tokyo, Fac Med, Dept Obstet & Gynecol, Tokyo 113, Japan
[4] Stanford Univ, Vet Affairs Palo Alto Hlth Care Syst, Dept Med, Div Endocrinol, Palo Alto, CA 94304 USA
关键词
D O I
10.1073/pnas.97.2.787
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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.
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页码:787 / 792
页数:6
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