Hormone-Sensitive Lipase Overexpression Increases Cholesteryl Ester Hydrolysis in Macrophage Foam Cells

Abstract

Abstract-Atherosclerosis is a complex physiopathologic process initiated by the formation of cholesterol-rich lesions in the arterial wall. Macrophages play a crucial role in this process because they accumulate large amounts of cholesterol esters (CEs) to form the foam cells that initiate the formation of the lesion and participate actively in the development of the lesion. Therefore, prevention or reversal of CE accumulation in macrophage foam cells could result in protection from multiple pathological effects. In this report, we show that the CE hydrolysis catalyzed 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 line, were found to be a suitable model of foam cell formation. HSL expression and nCEH activity in these cells and in peritoneal macrophages were comparable. In addition, antibody titration showed that essentially all nCEH activity in murine macrophages was accounted for by HSL. To examine the effect of HSL overexpression on foam cell formation, RAW 264.7 cells were stably transfected with a rat HSL cDNA. The resulting HSL overexpression increased hydrolysis of cellular CEs 2-to 3-fold in lipid-laden cells in the presence of an acyl coenzyme A:cholesterol acyltransferase (ACAT) inhibitor. Furthermore, addition of cAMP produced a 5-fold higher rate of CE hydrolysis in cholesterol-laden, HSL-overexpressing cells than in control cells and resulted in nearly complete hydrolysis of cellular CEs in only 9 hours, compared with Ͻ50% hydrolysis in control cells.

Identification of Neutral Cholesterol Ester Hydrolase, a Key Enzyme Removing Cholesterol from Macrophages

“…Second, HSL expression is regulated coordinately with nCEH activity in murine macrophages (13). Third, we (14) and others (15) demonstrated that overexpression of HSL is associated with increased hydrolysis of CE stores in THP-1 and RAW264.7 macrophages.…”

The Role of Neutral Cholesterol Ester Hydrolysis in Macrophage Foam Cells

“…Overexpression of macrophage LIPE in vivo using transgenic technology gave a somewhat complicated result. Overexpression of LIPE resulted in a paradoxical increase in atherosclerotic lesion development 11) , which could be reversed by the concomitant co-overexpression of a cholesterol acceptor, apoA- 45) . In contrast to LIPE, overexpression of CEH was reported to reduce atherosclerosis in LDL receptordeficient mice 28) .…”

“…Previously, it was believed that hormone-sensitive lipase (LIPE) was responsible for nCEH activity in macrophages [9][10][11] . LIPE is an intracellular neutral lipase that catalyzes the hydrolysis of triacylglycerol, diacylglycerol, monoacylglycerol, and CE as well as other lipids.…”

Small Dense Low Density Lipoprotein Sebagai Prediktor Risiko Penyakit Jantung Koroner pada Anak Lelaki Obes Pra-Pubertal

“…Gangguan pada pengaturan HSL dapat menjadi awal untuk terjadinya sel busa yang akan menyebabkan terjadinya aterosklerosis. 14,15 Pada penelitian kami, sebagian besar subjek mengalami hiperleptinemia seperti yang ditemukan pada individu dewasa obes. Pada dewasa obes keadaan hiperleptinemia ini berarti terjadi resitensi leptin, dengan demikian kemampuan leptin untuk berperan dalam metabolisme lemak terganggu.…”