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Papers In Press, published online ahead of print September 1, 2005
J. Lipid Res., doi:10.1194/jlr.M500081-JLR200

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Journal of Lipid Research, Vol. 46, 1860-1867, September 2005
Copyright © 2005 by American Society for Biochemistry and Molecular Biology

Human hormone-sensitive lipase (HSL): expression in white fat corrects the white adipose phenotype of HSL-deficient mice

Mélanie Fortier^*, Krishnakant Soni^*, Nancy Laurin^1,*, Shu Pei Wang^*, Pascale Mauriège, Frank R. Jirik and Grant A. Mitchell^2,*

^* Division of Medical Genetics, Research Centre, Sainte-Justine Hospital, Montréal, Québec, Canada
Division of Kinesiology, Department of Social and Preventive Medicine, Laval University, Ste-Foy, Quebec, Canada
Department of Biochemistry and Molecular Biology, University of Calgary, Calgary, Alberta, Canada

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-JLR200

¹ Present address of N. Laurin: Cell and Molecular Biology Division, Toronto Western Research Institute, University Health Network, Toronto, Ontario, Canada M5G 2C4.

² To whom correspondence should be addressed. e-mail: grant.mitchell{at}recherche-ste-justine.qc.ca

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 ß-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 ß-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.

Abbreviations: aP2, adipocyte fatty acid binding protein; DG, diglyceride; HSL, hormone-sensitive lipase; HSL^–/–, hormone-sensitive lipase-deficient; TG, triglyceride; WAT, white adipose tissue

Supplementary key words hormone-sensitive lipase • adipocyte • mouse • mutation • fat metabolism

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