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Human hormone-sensitive lipase (HSL): expression in white fat corrects the white adipose phenotype of HSL-deficient mices⃞s⃞ The online version of this article (available at http://www.jlr.org) contains an additional table. Published, JLR Papers in Press, June 16, 2005. DOI 10.1194/jlr.M500081-JLR20

M. Fortier,Krishnakant G. Soni,N. Laurin,Shu Pei Wang,P. Mauriège,F. Jirik,G. Mitchell

Published 2005 in Journal of Lipid Research

ABSTRACT

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 β-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 β-adrenergic agents. In contrast, HSL−/− ML and HSL−/−MH mice resembled nontransgenic HSL−/− 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.

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