Pancreatic carboxyl ester lipase: a circulating enzyme that modifies normal and oxidized lipoproteins in vitro.

Abstract

Pancreatic carboxyl ester lipase (CEL) hydrolyzes cholesteryl esters (CE), triglycerides (TG), and lysophospholipids, with CE and TG hydrolysis stimulated by cholate. Originally thought to be confined to the gastrointestinal system, CEL has been reported in the plasma of humans and other mammals, implying its potential in vivo to modify lipids associated with LDL, HDL (CE, TG), and oxidized LDL (lysophosphatidylcholine, lysoPC). We measured the concentration of CEL in human plasma as 1.2 Ϯ 0.5 ng/ml (in the range reported for lipoprotein lipase). Human LDL and HDL 3 reconstituted with radiolabeled lipids were incubated with purified porcine CEL without or with cholate (10 or 100 M, concentrations achievable in systemic or portal plasma, respectively). Using a saturating concentration of lipoprotein-associated CE (4 M), with increasing cholate concentration there was an increase in the hydrolysis of LDL-and HDL 3 -CE; at 100 M cholate, the percent hydrolysis per hour was 32 Ϯ 2 and 1.6 Ϯ 0.1, respectively, indicating that CEL interaction varied with lipoprotein class. HDL 3 -TG hydrolysis was also observed, but was only ‫ف‬ 5-10% of that for HDL 3 -CE at either 10 or 100 M cholate. Oxidized LDL (OxLDL) is enriched with lysoPC, a proatherogenic compound. After a 4-h incubation with CEL, the lysoPC content of OxLDL was depleted 57%. Colocalization of CEL in the vicinity of OxLDL formation was supported by demonstrating in human aortic homogenate a cholate-stimulated cholesteryl ester hydrolytic activity inhibited by anti-human CEL IgG. We conclude that CEL has the capability to modify normal human LDL and HDL composition and structure and to reduce the atherogenicity of OxLDL by decreasing its lysoPC content.

Modified Low Density Lipoprotein Enhances the Secretion of Bile Salt-stimulated Cholesterol Esterase by Human Monocyte-Macrophages

“…Results showing the presence of the cholesterol esterase in human aorta (17), and its increased secretion by oxidized LDL-stimulated human macrophages (Fig. 3), suggested its possible role in atherogenesis.…”

“…The mRNA for bile salt-stimulated cholesterol esterase was also present in human eosinophils (42). Bile salt-stimulated cholesterol esterase activity, which could be inhibited by antibodies specific for the pancreatic enzyme, was also reported to be present in human serum and in the aorta (16,17). These results suggested that bile saltstimulated cholesterol esterase may have a systemic origin and participates in systemic lipid metabolism, in addition to its role for nutrient digestion and transport in the gastrointestinal tract (43).…”

“…Previously, in an in vitro study, Shamir et al (17) showed the ability of the cholesterol esterase to hydrolyze lysophosphatidylcholine in oxidized LDL. Because lysophosphatidylcholine has been implicated as a contributing factor in atherosclerosis (50), the oxidized LDLinduced cholesterol esterase secretion by human macrophages may be a protective response against the atherogenic effects of the modified lipoproteins (17). However, it is equally possible that the bile salt-stimulated cholesterol esterase secreted by human macrophages may hydrolyze lipoprotein-associated cholesteryl esters and lipid-rich debris deposited on the arterial wall, thereby increasing cholesterol monohydrate formation and promotes atherosclerosis.…”

“…Although this protein is synthesized predominantly in the pancreas and lactating mammary glands in a form that is secreted from the cells (14), a significant amount of intracellular enzyme was also detectable in cells expressing the bile salt-stimulated cholesterol esterase mRNA (15). In view of the recent observations that the pancreatic type of cholesterol esterase (the bile saltstimulated lipase/cholesterol esterase) is present in human serum (16), and that its serum activity may participate in lipoprotein remodeling (16,17), this study was undertaken to determine if the bile salt-stimulated cholesterol esterase is expressed in macrophages.…”

Site-directed Mutagenesis of the Basic N-terminal Cluster of Pancreatic Bile Salt-dependent Lipase

“…BSDL is synthesized to a limited extent by human-monocytes-macrophages (32), endothelial cells (33,34), eosinophils (35), and the liver (22,36,37). BSDL has also been localized in necrotic areas of the pancreas, consecutive to an acute pancreatitis (38).…”