Alternative titles; symbols
HGNC Approved Gene Symbol: LIPG
Cytogenetic location: 18q21.1 Genomic coordinates (GRCh38) : 18:49,561,479-49,599,185 (from NCBI)
Endothelial lipase regulates the circulating level of high density lipoprotein cholesterol (HDL-C). It can also form a molecular bridge between endothelial cells and lipoproteins or circulating macrophages through interaction with heparan sulfate proteoglycans. This nonenzymatic action can increase cellular lipoprotein uptake and monocyte adhesion and contribute to atherosclerosis (summary by Ishida et al., 2004).
HDL-C levels are inversely associated with the risk of atherosclerotic cardiovascular disease. At least 50% of the variation in HDL cholesterol levels is genetically determined. Lipoprotein lipase (LPL; 609708) and hepatic lipase (HL, or LIPC; 151670), 2 members of the triacylglycerol (TG) lipase family, both influence HDL metabolism, and the HL locus has been associated with variation of HDL levels in humans. Jaye et al. (1999) described the cloning and in vivo functional analysis of a novel human TG lipase synthesized by endothelial cells in vitro, and thus named endothelial lipase (EL). The EL protein sequence is 45%, 40%, and 27% identical to those of LPL, HL, and pancreatic lipase (PL), respectively. Like other TG lipases, the EL protein commences with an 18-residue hydrophobic sequence characteristic of a secretory signal peptide. The 482-amino acid sequence contains the characteristic GXSXG lipase motif, a conserved catalytic triad, conserved heparin and lipoprotein binding sites, and 5 potential N-linked glycosylation sites. Cysteine residues, implicated in disulfide bonds necessary for enzymatic activity of other TG lipases, are conserved. Unlike LPL and HL, EL has a lid region of only 19 residues. The lid domain forms an amphipathic helix covering the catalytic pocket of the enzyme and confers substrate specificity to the enzymes of this family. Northern blot analysis detected a 4.5-kb EL transcript in liver, lung, kidney, placenta, and testis, but not in heart or skeletal muscle.
Using a PCR-based subtraction hybridization methodology, Hirata et al. (1999) cloned human and mouse cDNA corresponding to the LIPG gene. Northern blot analysis detected a 4.4-kb mRNA in placenta, liver, lung, ovary, thyroid, and testis. Expression was also seen in human umbilical vein and coronary endothelial cells and murine yolk sac cells.
By searching for genes upregulated in human umbilical vein endothelial cells, Ishida et al. (2004) cloned 2 splice variants of LIPG, which they designated EDL2a and EDL2b. Both variants encode truncated proteins that lack the first 80 amino acids of full-length LIPG, which the authors called EDL1a. In addition, EDL2b also lacks a 74-amino acid region that encodes a portion of the lid domain. RT-PCR confirmed expression of the truncated isoforms in several human tissues and cultured cells. Western blot analysis and immunofluorescence studies of stably transfected cells indicated that both truncated variants localized to the cytosol, while full-length LIPG was secreted into the culture medium.
Jaye et al. (1999) showed that EL has substantial phospholipase activity, but less triglyceride lipase activity. Overexpression of EL in mice reduced plasma concentration of HDL cholesterol and its major protein, apolipoprotein A-1 (107680). The endothelial expression, enzymatic profile and in vivo effects of EL suggested to Jaye et al. (1999) that it may have a role in lipoprotein metabolism and vascular biology.
Ishida et al. (2003) and Jin et al. (2003) found that a decrease in endothelial lipase expression and activity, by gene deletion and antibody inhibition, respectively, resulted in significant increases in plasma HDL cholesterol particles in mice. The findings of both studies showed that endothelial lipase is an important enzyme in the physiologic regulation of HDL metabolism.
Ishida et al. (2004) determined that the LIPG gene contains 11 exons and spans about 71.4 kb.
By genomic sequence analysis, Ishida et al. (2004) mapped the LIPG gene to chromosome 18q21.1.
Yamakawa-Kobayashi et al. (2003) detected 2 common SNPs in the LIPG gene associated with serum HDL-C levels in healthy school-aged children. The data supported the hypothesis that variations in this gene are one of the genetic determinants of HDL-C levels.
Ishida et al. (2004) found that Lipg expression was increased in apoE (107741) -/- mice, which were prone to the development of atherosclerotic vascular disease compared with control mice. Atherosclerotic lesions were markedly attenuated in apoE -/- Lipg -/- double-knockout mice compared with apoE -/- single-knockout mice; however, serum lipid profiling did not provide a clear mechanism for this effect since both antiatherogenic HDL and atherogenic VLDL/LDL levels were increased. Lipg was predominantly expressed by luminal endothelial cells and by infiltrating monocytes/macrophages in adventitia and atherosclerotic plaques. ApoE -/- Lipg -/- mice showed reduced macrophage infiltration compared with apoE -/- animals. Ex vivo adhesion assays revealed that monocyte/macrophage binding to apoE -/- Lipg -/- aortic strips was significantly less than to strips from apoE -/- mice. Heparin treatment significantly diminished the augmented cell adhesion to aortic strips from apoE -/- mice, but not to those from apoE -/- Lipg -/- mice, suggesting that upregulation of Lipg in aorta may enhance cell adhesion to the vessel wall by interaction with heparan sulfate proteoglycans.
Hirata, K., Dichek, H. L., Cioffi, J. A., Choi, S. Y., Leeper, N. J., Quintana, L., Kronmal, G. S., Cooper, A. D., Quertermous, T. Cloning of a unique lipase from endothelial cells extends the lipase gene family. J. Biol. Chem. 274: 14170-14175, 1999. [PubMed: 10318835] [Full Text: https://doi.org/10.1074/jbc.274.20.14170]
Ishida, T., Choi, S., Kundu, R. K., Hirata, K., Rubin, E. M., Cooper, A. D., Quertermous, T. Endothelial lipase is a major determinant of HDL level. J. Clin. Invest. 111: 347-355, 2003. [PubMed: 12569160] [Full Text: https://doi.org/10.1172/JCI16306]
Ishida, T., Choi, S. Y., Kundu, R. K., Spin, J., Yamashita, T., Hirata, K., Kojima, Y., Yokoyama, M., Cooper, A. D., Quertermous, T. Endothelial lipase modulates susceptibility to atherosclerosis in apolipoprotein-E-deficient mice. J. Biol. Chem. 279: 45085-45092, 2004. [PubMed: 15304490] [Full Text: https://doi.org/10.1074/jbc.M406360200]
Ishida, T., Zheng, Z., Dichek, H. L., Wang, H., Moreno, I., Yang, E., Kundu, R. K., Talbi, S., Hirata, K., Leung, L. L., Quertermous, T. Molecular cloning of nonsecreted endothelial cell-derived lipase isoforms. Genomics 83: 24-33, 2004. [PubMed: 14667806] [Full Text: https://doi.org/10.1016/s0888-7543(03)00181-2]
Jaye, M., Lynch, K. J., Krawiec, J., Marchadier, D., Maugeais, C., Doan, K., South, V., Amin, D., Perrone, M., Rader, D. J. A novel endothelial-derived lipase that modulates HDL metabolism. Nature Genet. 21: 424-428, 1999. [PubMed: 10192396] [Full Text: https://doi.org/10.1038/7766]
Jin, W., Millar, J. S., Broedl, U., Glick, J. M., Rader, D. J. Inhibition of endothelial lipase causes increased HDL cholesterol levels in vivo. J. Clin. Invest. 111: 357-362, 2003. [PubMed: 12569161] [Full Text: https://doi.org/10.1172/JCI16146]
Yamakawa-Kobayashi, K., Yanagi, H., Endo, K., Arinami, T., Hamaguchi, H. Relationship between serum HDL-C levels and common genetic variants of the endothelial lipase gene in Japanese school-aged children. Hum. Genet. 113: 311-315, 2003. [PubMed: 12884003] [Full Text: https://doi.org/10.1007/s00439-003-0985-6]