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      Role of Hepatic Lipase and Endothelial Lipase in High-Density Lipoprotein—Mediated Reverse Cholesterol Transport

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          Abstract

          Reverse cholesterol transport (RCT) constitutes a key part of the atheroprotective properties of high-density lipoproteins (HDL). Hepatic lipase (HL) and endothelial lipase (EL) are negative regulators of plasma HDL cholesterol levels. Although overexpression of EL decreases overall macrophage-to-feces RCT, knockout of both HL and EL leaves RCT essentially unaffected. With respect to important individual steps of RCT, current data on the role of EL and HL in cholesterol efflux are not conclusive. Both enzymes increase hepatic selective cholesterol uptake; however, this does not translate into altered biliary cholesterol secretion, which is regarded the final step of RCT. Also, the impact of HL and EL on atherosclerosis is not clear cut; rather it depends on respective experimental conditions and chosen models. More mechanistic insights into the diverse biological properties of these enzymes are therefore required to firmly establish EL and HL as targets for the treatment of atherosclerotic cardiovascular disease.

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          Most cited references47

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          A novel endothelial-derived lipase that modulates HDL metabolism.

          High-density lipoprotein (HDL) cholesterol levels are inversely associated with risk of atherosclerotic cardiovascular disease. At least 50% of the variation in HDL cholesterol levels is genetically determined, but the genes responsible for variation in HDL levels have not been fully elucidated. Lipoprotein lipase (LPL) and hepatic lipase (HL), two members of the triacylglyerol (TG) lipase family, both influence HDL metabolism and the HL (LIPC) locus has been associated with variation in HDL cholesterol levels in humans. We describe here the cloning and in vivo functional analysis of a new member of the TG lipase family. In contrast to other family members, this new lipase is synthesized by endothelial cells in vitro and thus has been termed endothelial lipase (encoded by the LIPG gene). EL is expressed in vivo in organs including liver, lung, kidney and placenta, but not in skeletal muscle. In contrast to LPL and HL, EL has a lid of only 19 residues. EL has substantial phospholipase activity, but less triglyceride lipase activity. Overexpression of EL in mice reduced plasma concentrations of HDL cholesterol and its major protein apolipoprotein A-I. The endothelial expression, enzymatic profile and in vivo effects of EL suggest that it may have a role in lipoprotein metabolism and vascular biology.
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            Hepatic lipase, lipoprotein metabolism, and atherogenesis.

            The role of hepatic lipase as a multifunctional protein that modulates lipoprotein metabolism and atherosclerosis has been extensively documented over the last decade. Hepatic lipase functions as a lipolytic enzyme that hydrolyzes triglycerides and phospholipids present in circulating plasma lipoproteins. Hepatic lipase also serves as a ligand that facilitates lipoprotein uptake by cell surface receptors and proteoglycans, thereby directly affecting cellular lipid delivery. Recently, another process by which hepatic lipase modulates atherogenic risk has been identified. Bone marrow transplantation studies demonstrate that hepatic lipase present in aortic lesions markedly alters aortic lesion formation even in the absence of changes in plasma lipids. These multiple functions of hepatic lipase, which facilitate not only plasma lipid metabolism but also cellular lipid uptake, can be anticipated to have a major and complex impact on atherogenesis. Consistently, human and animal studies support proatherogenic and antiatherogenic roles for hepatic lipase. The concept of hepatic lipase as mainly a lipolytic enzyme that reduces atherogenic risk has evolved into that of a complex protein with multiple functions that, depending on genetic background and sites of expression, can have a variable effect on atherosclerosis.
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              Cloning of a unique lipase from endothelial cells extends the lipase gene family.

              A new lipoprotein lipase-like gene has been cloned from endothelial cells through a subtraction methodology aimed at characterizing genes that are expressed with in vitro differentiation of this cell type. The conceptual endothelial cell-derived lipase protein contains 500 amino acids, including an 18-amino acid hydrophobic signal sequence, and is 44% identical to lipoprotein lipase and 41% identical to hepatic lipase. Comparison of primary sequence to that of lipoprotein and hepatic lipase reveals conservation of the serine, aspartic acid, and histidine catalytic residues as well as the 10 cysteine residues involved in disulfide bond formation. Expression was identified in cultured human umbilical vein endothelial cells, human coronary artery endothelial cells, and murine endothelial-like yolk sac cells by Northern blot. In addition, Northern blot and in situ hybridization analysis revealed expression of the endothelial-derived lipase in placenta, liver, lung, ovary, thyroid gland, and testis. A c-Myc-tagged protein secreted from transfected COS7 cells had phospholipase A1 activity but no triglyceride lipase activity. Its tissue-restricted pattern of expression and its ability to be expressed by endothelial cells, suggests that endothelial cell-derived lipase may have unique functions in lipoprotein metabolism and in vascular disease.
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                Author and article information

                Contributors
                +31-50-3611409 , +31-50-3611746 , w.annema@med.umcg.nl
                +31-50-3636762 , +31-50-3611746 , u_tietge@yahoo.com
                Journal
                Curr Atheroscler Rep
                Current Atherosclerosis Reports
                Current Science Inc. (New York )
                1523-3804
                1534-6242
                22 March 2011
                22 March 2011
                June 2011
                : 13
                : 3
                : 257-265
                Affiliations
                Department of Pediatrics, Center for Liver, Digestive, and Metabolic Diseases, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands
                Article
                175
                10.1007/s11883-011-0175-2
                3085744
                21424685
                7bd1663f-a80b-4dfc-99b3-a226c9ee301d
                © The Author(s) 2011
                History
                Categories
                Article
                Custom metadata
                © Springer Science+Business Media, LLC 2011

                Immunology
                macrophage-to-feces,bile,liver,efflux,cholesterol,triglycerides,hepatic lipase,macrophage,feces,phospholipase,risk,cardiovascular disease,atherosclerosis,therapy,endothelial lipase,high density lipoproteins,reverse cholesterol transport,inflammation

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