HORMONE-SENSITIVE LIPASE OVEREXPRESSION INCREASES CHOLESTERYL ESTER HYDROLYSIS IN MACROPHAGE FOAM CELLS

Atherosclerosis is a complex physiopathologic process initiated by the formation of cholesterol-rich lesions in the arterial wall. Macrophag es play a crucial role in this process because they accumulate large a mounts of cholesterol esters (CEs) to form the foam cells that initiat e the formation of the lesion and participate actively in the developm ent of the lesion: Therefore, prevention or reversal of CE accumulatio n in macrophage foam cells could result in protection from multiple pa thological effects. In this report, we show that the CE hydrolysis cat alyzed by neutral cholesterol ester hydrolase (nCEH) can be modulated by overexpression of hormone-sensitive lipase (HSL) in macrophage foam cells. For these studies, RAW 264.7 cells, a murine macrophage cell l ine, were found to be a suitable model of foam cell formation. HSL exp ression and nCEH activity in these cells and in peritoneal macrophages were comparable. In addition, antibody titration showed that essentia lly all nCEH activity in murine macrophages was accounted for by HSL. To examine the effect of HSL overexpression on foam cell formation, RA W 264.7 cells were stably transfected with a rat HSL cDNA. The resulti ng HSL overexpression increased hydrolysis of cellular CEs 2- to 3-fol d in lipid-laden cells in the presence of an acyl coenzyme A:cholester ol acyltransferase (ACAT) inhibitor. Furthermore, addition of cAMP pro duced a 5-fold higher rate of CE hydrolysis in cholesterol-laden, HSL- overexpressing cells than in control cells and resulted in nearly comp lete hydrolysis of cellular CEs in only 9 hours, compared with <50% hy drolysis in control cells. Thus, HSL overexpression stimulated the net hydrolysis of CEs, leading to faster hydrolysis of lipid deposits in model foam cells. These data suggest that HSL overexpression in macrop hages, alone or in combination with ACAT inhibitors, may constitute a useful therapeutic approach for impeding CE accumulation in macrophage s in vivo.