Generation and characterization of conventional and conditional knock-out mice lacking hormone-sensitive-lipase

Research project P 14309 HLS Knock-out Mice Rudolf ZECHNER 08.05.2000 Adipose tissue represents the largest energy depot in the body of mammals. For fat mobilization, hormone-sensitive lipase (HSL) can hydrolyze adipocyte triglycerides and release free fatty acids. Due to this key function in adipocyte metabolism, HSL may be involved in the regulation of adipose tissue mass and body composition. In addition to adipose tissue, HSL is expressed in several other cells and organs including macrophages, testis, muscle, adrenals, ovaries, brain, and pancreatic ß-cells. The physiological function of the enzyme in these tissues, however, is mostly unknown. Interestingly, HSL has also been shown to hydrolyze cholesteryl esters which renders the enzyme potentially important in the maintenance of the cellular cholesterol homeostasis, reverse cholesterol transport and steroid hormone synthesis. To date, however, in vivo evidence is lacking to support the involvement of HSL in these processes. The objective of the proposed project is to investigate the physiological- and pathophysiological function of HSL in adipose tissue, macrophages and testis using gene knock-out and transgenic mouse models. In preparation for this project, gene knock-out technology has been utilized to generate mice that lack functional HSL or carry loxP flanked exons of the HSL gene which will allow its tissue specific deletion. These animals will be used to elucidate the morphological, histopathological, and metabolic consequences of HSL deficiency in mice. The goals of the project are: * to generate conventional and conditional HSL knock-out mice, * to characterize the effects of HSL deficiency on adipose tissue development and metabolism, * to investigate the lipid and energy metabolism in HSL deficient mice, * to elucidate the role of macrophage HSL in the formation of foam cells and atherosclerotic lesions, * to reveal the function of HSL in testis. The proposed work will largely contribute to the understanding of HSL in lipid and energy metabolism, macrophage function and spermatogenesis and offer important insights into the pathogenesis of obesity and atherosclerosis. is.