CoChat
Sign Up
Cited by 1Lipid metabolism and disordersParaoxonase enzyme and polymorphismsLipoproteins and Cardiovascular Health

The DOI matches its Crossref record; 2 of the 2 references it cites were found in a registry or an index.

Endothelial lipase variant T111I does not alter inhibition by angiopoietin-like proteins

Open access
Sylvers-Davie, Kelli L., Bierstedt, Kaleb C., Schnieders, Michael J., Davies, Brandon S. J.·2024·Scientific Reports
DOI 10.1038/s41598-024-54705-6PMC PMC10879187

Published version of a preprint

Open this paper in CoChat — free accountOpen PDF

Abstract

High levels of HDL-C are correlated with a decreased risk of cardiovascular disease. HDL-C levels are modulated in part by the secreted phospholipase, endothelial lipase (EL), which hydrolyzes the phospholipids of HDL and decreases circulating HDL-C concentrations. A 584C/T polymorphism in LIPG , the gene which encodes EL, was first identified in individuals with increased HDL levels. This polymorphism results in a T111I point mutation the EL protein. The association between this variant, HDL levels, and the risk of coronary artery disease (CAD) in humans has been extensively studied, but the findings have been inconsistent. In this study, we took a biochemical approach, investigating how the T111I variant affected EL activity, structure, and stability. Moreover, we tested whether the T111I variant altered the inhibition of phospholipase activity by angiopoietin-like 3 (ANGPTL3) and angiopoietin-like 4 (ANGPTL4), two known EL inhibitors. We found that neither the stability nor enzymatic activity of EL was altered by the T111I variant. Moreover, we found no difference between wild-type and T111I EL in their ability to be inhibited by ANGPTL proteins. These data suggest that any effect this variant may have on HDL-C levels or cardiovascular disease are not mediated through alterations in these functions.

Overview

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1038/s41598-024-54705-6

Cites

2 of 2 references verified0 citation errors · 0 not checkable

Statistics

Verification

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Citations

Cites

Flagged first, then by citations

Research works printed but not linked: 58

  1. Tall, A. R. An overview of reverse cholesterol transport. Eur. Heart J. 19(Suppl A), A31-35 (1998).
  2. Wang, N., Lan, D., Chen, W., Matsuura, F. & Tall, A. R. ATP-binding cassette transporters G1 and G4 mediate cellular cholesterol efflux to high-density lipoproteins. Proc. Natl. Acad. Sci. U.S.A. 101, 9774–9779 (2004). · DOI
  3. Larrede, S. et al. Stimulation of cholesterol efflux by LXR agonists in cholesterol-loaded human macrophages is ABCA1-dependent but ABCG1-independent. Arterioscler. Thromb. Vasc. Biol. 29, 1930–1936 (2009). · DOI
  4. Tarling, E. J. & Edwards, P. A. ATP binding cassette transporter G1 (ABCG1) is an intracellular sterol transporter. Proc. Natl. Acad. Sci. U.S.A. 108, 19719–19724 (2011). · DOI
  5. Bowry, V. W., Stanley, K. K. & Stocker, R. High density lipoprotein is the major carrier of lipid hydroperoxides in human blood plasma from fasting donors. Proc. Natl. Acad. Sci. U.S.A. 89, 10316–10320 (1992). · DOI
  6. Hirata, K. et al. Cloning of a unique lipase from endothelial cells extends the lipase gene family. J. Biol. Chem. 274, 14170–14175 (1999). · DOI
  7. Jahangiri, A. et al. Evidence that endothelial lipase remodels high density lipoproteins without mediating the dissociation of apolipoprotein A-I. J. Lipid Res. 46, 896–903 (2005). · DOI
  8. Jaye, M. et al. A novel endothelial-derived lipase that modulates HDL metabolism. Nat. Genet. 21, 424–428 (1999). · DOI · Paper page
  9. Ishida, T. et al. Endothelial lipase is a major determinant of HDL level. J. Clin. Investig. 111, 347–355 (2003). · DOI
  10. Ma, K. et al. Endothelial lipase is a major genetic determinant for high-density lipoprotein concentration, structure, and metabolism. Proc. Natl. Acad. Sci. 100, 2748–2753 (2003). · DOI · Paper page
  11. deLemos, A. S., Wolfe, M. L., Long, C. J., Sivapackianathan, R. & Rader, D. J. Identification of genetic variants in endothelial lipase in persons with elevated high-density lipoprotein cholesterol. Circulation 106, 1321–1326 (2002). · DOI
  12. Mank-Seymour, A. R., Durham, K. L., Thompson, J. F., Seymour, A. B. & Milos, P. M. Association between single-nucleotide polymorphisms in the endothelial lipase (LIPG) gene and high-density lipoprotein cholesterol levels. Biochim. Biophys. Acta 1636, 40–46 (2004). · DOI
  13. Hutter, C. M. et al. Association of endothelial lipase gene (LIPG) haplotypes with high-density lipoprotein cholesterol subfractions and apolipoprotein AI plasma levels in Japanese Americans. Atherosclerosis 185, 78–86 (2006). · DOI
  14. Tang, N.-P. et al. Protective effect of an endothelial lipase gene variant on coronary artery disease in a Chinese population. J. Lipid Res. 49, 369–375 (2008). · DOI
  15. Paradis, M.-E. et al. The T111I mutation in the EL gene modulates the impact of dietary fat on the HDL profile in women. J. Lipid Res. 44, 1902–1908 (2003). · DOI
  16. Solim, L. A. et al. Endothelial lipase gene polymorphism (584 C/T) in coronary artery patients among a Turkish population. In Vivo 32, 1105–1109 (2018). · DOI
  17. Cai, G., Huang, Z., Zhang, B., Weng, W. & Shi, G. The associations between endothelial lipase 584C/T polymorphism and HDL-C level and coronary heart disease susceptibility: A meta-analysis. Lipids Health Dis. 13, 85 (2014). · DOI
  18. Halverstadt, A. et al. High-density lipoprotein-cholesterol, its subfractions, and responses to exercise training are dependent on endothelial lipase genotype. Metabolism 52, 1505–1511 (2003). · DOI
  19. Shimizu, M. et al. Endothelial lipase gene polymorphism is associated with acute myocardial infarction, independently of high-density lipoprotein-cholesterol levels. Circ. J. 71, 842–846 (2007). · DOI
  20. Jensen, M. K. et al. The T111I variant in the endothelial lipase gene and risk of coronary heart disease in three independent populations. Eur. Heart J. 30, 1584–1589 (2009). · DOI
  21. 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). · DOI
  22. Razzaghi, H., Santorico, S. A. & Kamboh, M. I. Population-based resequencing of LIPG and ZNF202 genes in subjects with extreme HDL levels. Front. Genet. 3, 89 (2012). · DOI
  23. Edmondson, A. C. et al. Loss-of-function variants in endothelial lipase are a cause of elevated HDL cholesterol in humans. J. Clin. Investig. 119, 1042–1050 (2009).
  24. Smith, C. E. et al. Physical inactivity interacts with an endothelial lipase polymorphism to modulate high density lipoprotein cholesterol in the GOLDN study. Atherosclerosis 206, 500–504 (2009). · DOI
  25. Shimamura, M. et al. Angiopoietin-like protein3 regulates plasma HDL cholesterol through suppression of endothelial lipase. Arterioscler. Thromb. Vasc. Biol. 27, 366–372 (2007). · DOI · Paper page
  26. Chi, X. et al. ANGPTL8 promotes the ability of ANGPTL3 to bind and inhibit lipoprotein lipase. Mol. Metab. 6, 1137–1149 (2017). · DOI · Paper page
  27. Lee, E.-C. et al. Identification of a new functional domain in angiopoietin-like 3 (ANGPTL3) and angiopoietin-like 4 (ANGPTL4) involved in binding and inhibition of lipoprotein lipase (LPL). J. Biol. Chem. 284, 13735–13745 (2009). · DOI · Paper page
  28. Shimizugawa, T. et al. ANGPTL3 decreases very low density lipoprotein triglyceride clearance by inhibition of lipoprotein lipase. J. Biol. Chem. 277, 33742–33748 (2002). · DOI · Paper page
  29. Shan, L. et al. The angiopoietin-like proteins ANGPTL3 and ANGPTL4 inhibit lipoprotein lipase activity through distinct mechanisms. J. Biol. Chem. 284, 1419–1424 (2009). · DOI · Paper page
  30. Sonnenburg, W. K. et al. GPIHBP1 stabilizes lipoprotein lipase and prevents its inhibition by angiopoietin-like 3 and angiopoietin-like 4. J. Lipid Res. 50, 2421–2429 (2009). · DOI · Paper page
  31. Yau, M. et al. A highly conserved motif within the NH2-terminal coiled-coil domain of angiopoietin-like protein 4 confers its inhibitory effects on lipoprotein lipase by disrupting the enzyme dimerization. J. Biol. Chem. 284, 11942–11952 (2009). · DOI · Paper page
  32. Jin, W. et al. Hepatic proprotein convertases modulate HDL metabolism. Cell Metab. 6, 129–136 (2007). · DOI · Paper page
  33. Mirdita, M., K. Schütze, Y. Moriwaki, L. Heo, S. Ovchinnikov, and M. Steinegger. ColabFold - Making protein folding accessible to all. https://www.biorxiv.org/content/https://doi.org/10.1101/2021.08.15.456425v2 (Accessed 26 November 2021) (2021). · DOI
  34. Razzaghi, H. et al. Genetic and structure-function studies of missense mutations in human endothelial lipase. PLoS One 8, e55716 (2013). · DOI
  35. Rodrigues, C. H. M., Pires, D. E. V. & Ascher, D. B. DynaMut2: Assessing changes in stability and flexibility upon single and multiple point missense mutations. Protein Sci. 30, 60–69 (2021). · DOI
  36. Rodrigues, C. H. M., Portelli, S. & Ascher, D. B. Exploring the effects of missense mutations on protein thermodynamics through structure-based approaches: Findings from the CAGI6 challenges. Hum. Genet. https://doi.org/10.1007/s00439-023-02623-4 (2024). · DOI
  37. Sylvers-Davie, K. L., Segura-Roman, A., Salvi, A. M., Schache, K. J. & Davies, B. S. J. Angiopoietin-like 3 inhibition of endothelial lipase is not modulated by angiopoietin-like 8. J. Lipid Res. 62, 100112 (2021). · DOI
  38. Leth-Espensen, K. Z. et al. The intrinsic instability of the hydrolase domain of lipoprotein lipase facilitates its inactivation by ANGPTL4-catalyzed unfolding. Proc. Natl. Acad. Sci. U.S.A. 118, e2026650118 (2021). · DOI · Paper page
  39. Mysling, S. et al. The angiopoietin-like protein ANGPTL4 catalyzes unfolding of the hydrolase domain in lipoprotein lipase and the endothelial membrane protein GPIHBP1 counteracts this unfolding. eLife https://doi.org/10.7554/eLife.20958 (2016). · DOI · Paper page
  40. Ge, H., Yang, G., Yu, X., Pourbahrami, T. & Li, C. Oligomerization state-dependent hyperlipidemic effect of angiopoietin-like protein 4. J. Lipid Res. 45, 2071–2079 (2004). · DOI · Paper page
  41. Lichtenstein, L. et al. Angptl4 protects against severe proinflammatory effects of saturated fat by inhibiting fatty acid uptake into mesenteric lymph node macrophages. Cell Metab. 12, 580–592 (2010). · DOI · Paper page
  42. Mandard, S. et al. The fasting-induced adipose factor/angiopoietin-like protein 4 is physically associated with lipoproteins and governs plasma lipid levels and adiposity. J. Biol. Chem. 281, 934–944 (2006). · DOI · Paper page
  43. Sukonina, V., Lookene, A., Olivecrona, T. & Olivecrona, G. Angiopoietin-like protein 4 converts lipoprotein lipase to inactive monomers and modulates lipase activity in adipose tissue. Proc. Natl. Acad. Sci. U.S.A. 103, 17450–17455 (2006). · DOI · Paper page
  44. Haller, J. F. et al. ANGPTL8 requires ANGPTL3 to inhibit lipoprotein lipase and plasma triglyceride clearance. J. Lipid Res. 58, 1166–1173 (2017). · DOI · Paper page
  45. Kovrov, O., Kristensen, K. K., Larsson, E., Ploug, M. & Olivecrona, G. On the mechanism of angiopoietin-like protein 8 for control of lipoprotein lipase activity. J. Lipid Res. 60, 783 (2019). · DOI · Paper page
  46. Chen, Y. Q. et al. Angiopoietin-like protein 8 differentially regulates ANGPTL3 and ANGPTL4 during postprandial partitioning of fatty acids. J. Lipid Res. 61, 1203 (2020). · DOI · Paper page
  47. Kristensen, K. K. et al. Unfolding of monomeric lipoprotein lipase by ANGPTL4: Insight into the regulation of plasma triglyceride metabolism. Proc. Natl. Acad. Sci. U.S.A. 117, 4337–4346 (2020). · DOI · Paper page
  48. Katoh, K. & Standley, D. M. MAFFT multiple sequence alignment software version 7: Improvements in performance and usability. Mol. Biol. Evol. 30, 772–780 (2013). · DOI · Paper page
  49. Chen, Y. Q. et al. Angiopoietin-like protein 4 (ANGPTL4) is an inhibitor of endothelial lipase (EL) while the ANGPTL4/8 complex has reduced EL-inhibitory activity. Heliyon 7, e07898 (2021). · DOI
  50. Fuki, I. V. et al. Endogenously produced endothelial lipase enhances binding and cellular processing of plasma lipoproteins via heparan sulfate proteoglycan-mediated pathway. J. Biol. Chem. 278, 34331–34338 (2003). · DOI
  51. Zhao, H., Zhao, R., Hu, S. & Rong, J. Gene polymorphism associated with angiotensinogen (M235T), endothelial lipase (584C/T) and susceptibility to coronary artery disease: A meta-analysis. Biosci. Rep. 40, BSR20201414 (2020). · DOI
  52. Wu, Y. et al. Significant association between the endothelial lipase gene 584C/T polymorphism and coronary artery disease risk. Biosci. Rep. https://doi.org/10.1042/BSR20200027 (2020). · DOI
  53. Strauss, J. G. et al. Endothelial cell-derived lipase mediates uptake and binding of high-density lipoprotein (HDL) particles and the selective uptake of HDL-associated cholesterol esters independent of its enzymic activity. Biochem. J. 368, 69–79 (2002). · DOI
  54. Chi, X. et al. Angiopoietin-like 4 modifies the interactions between lipoprotein lipase and its endothelial cell transporter GPIHBP1. J. Biol. Chem. 290, 11865–11877 (2015). · DOI · Paper page
  55. Dull, T. et al. A third-generation lentivirus vector with a conditional packaging system. J. Virol. 72, 8463–8471 (1998). · DOI · Paper page
  56. Basu, D., Lei, X., Josekutty, J., Hussain, M. M. & Jin, W. Measurement of the phospholipase activity of endothelial lipase in mouse plasma. J. Lipid Res. 54, 282–289 (2013). · DOI
  57. Michell, D. L. et al. Isolation of high-density lipoproteins for non-coding small RNA quantification. J. Vis. Exp. https://doi.org/10.3791/54488 (2016). · DOI
  58. UniProt Consortium. UniProt: The universal protein knowledgebase in 2021. Nucleic Acids Res. 49, D480–D489 (2021). · DOI · Paper page

Metadata

Authors
Sylvers-Davie, K. L., Bierstedt, K. C., Schnieders, M. J., & Davies, B. S. J.
Affiliations
University of Iowa (US)
Corresponding author
Davies, Brandon S. J.
ORCID
Venue
Scientific Reports
Publisher
Springer Science and Business Media LLC
Published
2024-02-20
Volume
14
Issue
1
Pages
4246-4246
ISSN
2045-2322 (ISSN-L)
DOI
10.1038/s41598-024-54705-6
PMC
PMC10879187
OpenAlex
W4391957770
Cited by
1
References
2
Citations by year
2025: 1
FWCI
0.30
Type
journal article
Language
en
Open access
Licence
Locations
  • Scientific Reports (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • PubMed Central (submittedVersion, cc-by-nc-nd)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Institutes of Health (T32DK112751, R01DC012049, R01HL162698)
  • National Science Foundation (CHE-1751688)
Topics
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Paraoxonase enzyme and polymorphisms
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipoproteins and Cardiovascular Health
Keywords
endothelial lipase, ANGPTL3, ANGPTL4, phospholipase inhibition, HDL cholesterol, coronary artery disease, protein stability, enzyme activity, genetic polymorphism

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review