Endothelial lipase

Choi, S.; Hirata, Ken‐ichi; Ishida, Tatsuro; Quertermous, Thomas; Cooper, Allen D.

doi:10.1194/jlr.r200011-jlr200

Cited by 81 publications

(22 citation statements)

References 64 publications

(53 reference statements)

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“…In a recent review article, Choi et al (33) commented on an unpublished study showing that mice homologous for EL-null alleles have elevated HDL cholesterol level, an observation that corroborates the data in the current study.…”

Section: El Sequence Variants Are Associated With Plasma Hdl Cholestesupporting

confidence: 75%

Endothelial lipase is a major genetic determinant for high-density lipoprotein concentration, structure, and metabolism

Çilingiroğlu

Otvos

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

217

220

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High-density lipoprotein (HDL) protects against atherosclerosis. Endothelial lipase (EL) has been postulated to be involved in lipoprotein, and possibly HDL, metabolism, yet the evidence has been scarce and conflicting. We have inactivated EL in mice by gene targeting. EL ؊/؊ mice have elevated plasma and HDL cholesterol, and increased apolipoproteins A-I and E. NMR analysis reveals an abundance of large HDL particles. There is down-regulation of the transcripts for phospholipid transfer protein, but up-regulation of those for hepatic lipase and lipoprotein lipase. Plasma lecithin:cholesterol acyltransferase is unchanged despite an increase in hepatic mRNA; lecithin:cholesterol acyltransferase activity toward endogenous EL ؊/؊ substrate is, however, reduced by 50%. HDL clearance is decreased in EL ؊/؊ mice; both the structure of HDL and the presence of EL are factors that determine the rate of clearance. To determine EL's role in humans, we find a significant association between a single-nucleotide polymorphism 584C͞T in the EL (LIPG) gene and HDL cholesterol in a well characterized population of 372 individuals. We conclude that EL is a major determinant of HDL concentration, structure, and metabolism in mice, and a major determinant of HDL concentration in humans.lipoprotein metabolism ͉ atherosclerosis ͉ gene targeting

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Section: El Sequence Variants Are Associated With Plasma Hdl Cholestesupporting

confidence: 75%

Endothelial lipase is a major genetic determinant for high-density lipoprotein concentration, structure, and metabolism

Çilingiroğlu

Otvos

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

217

220

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“…Consequently, EL expression is closely linked with the pathogenesis of atherosclerosis. EL expression is subject to many factors, and can be increased by shear forces that induce inflammation and blood pressure [23], [24]. However, the precise mechanisms that underlie the regulation of EL expression are not fully elucidated.…”

Section: Introductionmentioning

confidence: 99%

Angiotensin II Upregulates Endothelial Lipase Expression via the NF-Kappa B and MAPK Signaling Pathways

Zhang¹,

Jiang

et al. 2014

PLoS ONE

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BackgroundAngiotensin II (AngII) participates in endothelial damage and inflammation, and accelerates atherosclerosis. Endothelial lipase (EL) is involved in the metabolism and clearance of high density lipoproteins (HDL), the serum levels of which correlate negatively with the onset of cardiovascular diseases including atherosclerosis. However, the relationship between AngII and EL is not yet fully understood. In this study, we investigated the effects of AngII on the expression of EL and the signaling pathways that mediate its effects in human umbilical vein endothelial cells (HUVECs).Methods and FindingsHUVECs were cultured in vitro with different treatments as follows: 1) The control group without any treatment; 2) AngII treatment for 0 h, 4 h, 8 h, 12 h and 24 h; 3) NF-κB activation inhibitor pyrrolidine dithiocarbamate (PDTC) pretreatment for 1 h before AngII treatment; and 4) mitogen-activated protein kinase (MAPK) p38 inhibitor (SB203580) pretreatment for 1 h before AngII treatment. EL levels in each group were detected by immunocytochemical staining and western blotting. HUVECs proliferation was detected by MTT and proliferating cell nuclear antigen (PCNA) immunofluorescence staining. NF-kappa B (NF-κB) p65, MAPK p38, c-Jun N-terminal kinase (JNK), extracellular signal-regulated kinase (ERK) and phosphorylated extracellular signal-regulated kinase (p-ERK) expression levels were assayed by western blotting. The results showed that the protein levels of EL, NF-κB p65, MAPK p38, JNK, and p-ERK protein levels, in addition to the proliferation of HUVECs, were increased by AngII. Both the NF-kB inhibitor (PDTC) and the MAPK p38 inhibitor (SB203580) partially inhibited the effects of AngII on EL expression.ConclusionAngII may upregulate EL protein expression via the NF-κB and MAPK signaling pathways.

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“…Like LPL and HL, the EL protein is secreted and binds to heparan sulfate proteoglycans on the endothelial cell surface, where it interacts with lipoproteins (13)(14)(15). Both overexpression and loss of function studies have shown that EL is important in the regulation of HDL cholesterol levels (16 -19).…”

mentioning

confidence: 99%

Proprotein Covertases Are Responsible for Proteolysis and Inactivation of Endothelial Lipase

Jin

Fuki

Seidah

et al. 2005

Journal of Biological Chemistry

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Plasma lipoprotein metabolism is tightly regulated by several members of the triglyceride lipase family, including endothelial lipase (EL) and lipoprotein lipase (LPL). Our previous work suggested that EL is proteolytically processed. In this report, we have used a combination of epitope tagging, mutagenesis, and N-terminal sequencing to determine the precise location of the cleavage site within EL. The cleavage occurs immediately after the sequence RNKR, a known recognition sequence for the proprotein convertase (PC) family. We demonstrate that some PCs, but not all, can proteolytically cleave EL at this site and thereby directly regulate EL enzymatic activity through modulating EL cleavage. Furthermore, specific knockdown of individual PCs proves that PCs are the proteases that cleave EL in human endothelial cells. Interestingly, a homologous site in LPL is also cleaved by PCs. This action is unusual for PCs, which are traditionally known as activators of pro-proteins, and highlights a potential role of PCs in lipid metabolism through their proteolytic processing of lipases.Site-specific proteolysis is crucial in regulating many fundamental biological pathways, including the sequential initiation of activation of blood coagulation factors and activation of caspases and digestive enzymes (1-3). The proprotein convertase (PC) 5 family is composed of at least nine members and belongs to the subtilisin superfamily of serine endoproteases (4). The basic amino acid-specific PCs catalyze the proteolytic maturation of a strikingly diverse collection of substrates at paired basic amino acid processing sites to generate biologically active molecules in the secretory pathway (5). Some PC substrates are proteins involved in lipid metabolism. Furin, the first discovered and best characterized PC, was shown to cleave the low density lipoprotein receptorrelated protein (6), and a mutation of the processing site of chicken low density lipoprotein receptor-related protein impaired efficient exit from the endoplasmic reticulum (7). Subtilisin-kexin isozyme-1/Site-1 protease (SKI-1/S1P), an early Golgi-localized PC (8), cleaves membranebound sterol regulatory element-binding proteins and releases the active subunit of sterol regulatory element-binding proteins to maintain cholesterol homeostasis (9).PCs were considered to be redundant because a large body of in vitro work had shown that several PCs could cleave the same substrate. Recently, lessons from the studies of neural apoptosis-regulated convertase 1 (NARC-1), a newly discovered PC (10, 11), reinforced the importance of individual PCs in regulating plasma lipid metabolism. However, the substrate of NARC-1 is not yet identified.Endothelial lipase (EL) is a recently described modulator of lipoprotein metabolism that belongs to the triglyceride lipase family, which also includes lipoprotein lipase (LPL) and hepatic lipase (HL) (12). Like LPL and HL, the EL protein is secreted and binds to heparan sulfate proteoglycans on the endothelial cell surface, where it interacts wit...

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Endothelial lipase

Cited by 81 publications

References 64 publications

Endothelial lipase is a major genetic determinant for high-density lipoprotein concentration, structure, and metabolism

Endothelial lipase is a major genetic determinant for high-density lipoprotein concentration, structure, and metabolism

Angiotensin II Upregulates Endothelial Lipase Expression via the NF-Kappa B and MAPK Signaling Pathways

Proprotein Covertases Are Responsible for Proteolysis and Inactivation of Endothelial Lipase

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