Genomics !!

Cholesteryl ester hydrolase in human monocyte/macrophage: cloning, sequencing, and expression of full-length cDNA



THE FORMATION of macrophage-derived foam cells is a central event in the development of fatty streaks within the arterial wall and progression of atherosclerosis. The unregulated uptake of modified lipoproteins by macrophages via scavenger-receptors leads to the deposition of cholesterol esters and the formation of foam cells. Stored cholesterol esters, present as cytoplasmic droplets, exist in dynamic equilibrium with unesterified cholesterol undergoing continuous hydrolysis and reesterification in a process known as the "cholesterol ester cycle." Neutral cholesteryl ester hydrolase (CEH) catalyzes the hydrolytic reaction, whereas reesterification is catalyzed by acyl-CoA cholesterol acyltransferase (ACAT). Free cholesterol released by CEH moves to the plasma membrane and is subsequently transferred to a cholesterol acceptor [e.g., high-density lipoprotein (HDL)], resulting in net cellular cholesterol efflux. Macrophages with high neutral CEH activity accumulate less cholesterol esters in the presence of atherogenic ß-migrating very low-density lipoproteins (ß-VLDL) in comparison to macrophages with low CEH activity . Animal models of atherosclerosis, such as the hypercholesterolemic rabbit and the White Carneau pigeon, appear to possess macrophages in which stored cholesterol esters are resistant to hydrolysis and subsequent mobilization . Hence, CEH activity may be a limiting factor in the mobilization of cholesterol esters from foam cells and therefore may play a role in determining the susceptibility to atherosclerosis.

Despite the obvious significance of cholesterol ester hydrolytic enzymes in atherogenesis, the identity of CEH in macrophages remains obscure. Several lines of evidence suggest that the enzyme responsible for cholesterol ester hydrolysis in murine macrophages is similar to hormone-sensitive lipase (HSL) present in adipose and steroidogenic tissues . Although Reue et al. detected HSL mRNA in the human monocyte cell line THP-1, Contreras et al. failed to detect HSL mRNA in human macrophages. Li and Hui recently reported the absence of HSL in human macrophages and demonstrated the expression of bile salt-stimulated CEH, similar to secretory pancreatic CEH. Since this enzyme was secreted from the cells, Li and Hui proposed that it was unlikely to play a role in the intracellular cholesterol metabolism and suggested that another CEH may be responsible for cholesteryl ester metabolism in human macrophages.