- •Macrophage-derived foam cells induced by LPA have a diminished capacity of migration.
- •Downregulation of Fut8 and α-1, 6-fucosylation levels is involved in the decreased mobility of foam cells.
- •LPA can reduce the combination between HNF1α and Fut8 promoter region by activating its LPA1, 3 receptors.
Background and aims
Aberrant fucosylation, such as α-1,6 fucosylation catalyzed by fucosyltransferase 8 (Fut8), is associated with reduced cell migration and is responsible for cholesterol-enriched foam cell accumulation in the intima in the early stage of atherosclerosis.
The current study evaluated the impact of glycosyltransferases on foam cell migration induced by lysophosphatidic acid (LPA) and its potential mechanism.
The mobility of foam cells was evaluated via transwell and scratch assays. The expression of Fut8 and α-1,6 fucosylation of proteins were assessed by RT-PCR, Western blotting, etc. Overexpression of Fut8 was used to explore the direct relationship between Fut8 and foam cell migration. Dual luciferase reporter assay was performed to determine whether the regulation of Fut8 by LPA occurred at the transcriptional level. Binding of hepatocyte nuclear factor 1-alpha (HNF1α) to the Fut8 promoter was assessed by electrophoretic mobility shift assay and chromatin immunoprecipitation assay.
We found that the migration capacity of foam cells induced by LPA was significantly decreased. Fut8 and α-1,6 fucosylation showed the most obvious decline after treatment with 200 μM LPA for 24 h. Overexpression of Fut8 was able to restore the foam cell migration capacity. Another important finding was that the LPA1 and LPA3 (LPA1,3) receptors were involved in the regulation of Fut8. It is interesting to note that LPA led to a decrease in Fut8 gene transcription activity, and HNF1α transcription factor played a positive role in downregulation of Fut8 promoter activity.
Our results strongly indicated that the LPA-LPA1, 3 receptor-HNF1α pathway is involved in the downregulation of Fut8, leading to diminished foam cell migration.
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- Heart disease and stroke statistics-2016 update: a report from the American heart association.Circulation. 2016; 133: e38-360
- Atherosclerosis. the road ahead.Cell. 2001; 104: 503-516
- CD36 modulates migration of mouse and human macrophages in response to oxidized LDL and may contribute to macrophage trapping in the arterial intima.J. Clin. Investig. 2009; 119: 136-145
- Macrophages in atherosclerosis: a dynamic balance.Nat. Rev. Immunol. 2013; 13: 709-721
- Emigration of monocyte-derived cells from atherosclerotic lesions characterizes regressive, but not progressive, plaques.Proc. Natl. Acad. Sci. U.S.A. 2004; 101: 11779-11784
- HDL promotes rapid atherosclerosis regression in mice and alters inflammatory properties of plaque monocyte-derived cells.Proc. Natl. Acad. Sci. U.S.A. 2011; 108: 7166-7171
- Analysis of protein glycosylation in the ER.Methods Mol. Biol. 2018; 1691: 205-222
- Glycobiology: more functions for oligosaccharides.Science. 1995; 269: 1234-1235
- Deficiency of the sialyltransferase St3Gal4 reduces Ccl5-mediated myeloid cell recruitment and arrest: short communication.Circ. Res. 2014; 114: 976-981
- TNF-alpha regulates the proteolytic degradation of ST6Gal-1 and endothelial cell-cell junctions through upregulating expression of BACE1.Sci. Rep. 2017; 7: 40256
- ST6GAL1 negatively regulates monocyte transendothelial migration and atherosclerosis development.Biochem. Biophys. Res. Commun. 2018; 500: 249-255
- Overexpression of alpha (1,6) fucosyltransferase associated with aggressive prostate cancer.Glycobiology. 2014; 24: 935-944
- Posttranslational modification of E-cadherin by core fucosylation regulates Src activation and induces epithelial-mesenchymal transition-like process in lung cancer cells.Glycobiology. 2016; 26: 142-154
- Decreased core-fucosylation contributes to malignancy in gastric cancer.PLoS One. 2014; 9e94536
- Lysophosphatidic acid directly induces macrophage-derived foam cell formation by blocking the expression of SRBI.Biochem. Biophys. Res. Commun. 2017; 491: 587-594
- Adipose differentiationrelated protein knockdown inhibits vascular smooth muscle cell proliferation and migration and attenuates neointima formation.Mol. Med. Rep. 2017; 16: 3079-3086
- Lysophosphatidic acid mediates the rapid activation of platelets and endothelial cells by mildly oxidized low density lipoprotein and accumulates in human atherosclerotic lesions.Proc. Natl. Acad. Sci. U. S. A. 1999; 96: 6931-6936
- Lysophosphatidic acid effects on atherosclerosis and thrombosis.Clin. Lipidol. 2011; 6: 413-426
- Glycosyltransferases, glycosylation and atherosclerosis.Glycoconj. J. 2014; 31: 605-611
- Lectin-based analysis of fucosylated glycoproteins of human skim milk during 47 days of lactation.Glycoconj. J. 2015; 32: 665-674
- Fucose: biosynthesis and biological function in mammals.Glycobiology. 2003; 13: 41R-53R
- Spontaneous hypercholesterolemia and arterial lesions in mice lacking apolipoprotein E.Science. 1992; 258: 468-471
- Diversity of cellular receptors and functions for the lysophospholipid growth factors lysophosphatidic acid and sphingosine 1-phosphate.FASEB J. : Off. Publ. Feder. Am. Soc. Exp. Biol. 1998; 12: 1589-1598
- Lysophosphatidic acid receptors LPA1 and LPA3 promote CXCL12-mediated smooth muscle progenitor cell recruitment in neointima formation.Circ. Res. 2010; 107: 96-105
- The mechanism by which cycloheximide and related glutarimide antibiotics inhibit peptide synthesis on reticulocyte ribosomes.J. Biol. Chem. 1971; 246: 174-181
- Genomics meets glycomics-the first GWAS study of human N-Glycome identifies HNF1alpha as a master regulator of plasma protein fucosylation.PLoS Genet. 2010; 6e1001256
- The emerging role of lysophosphatidic acid in cancer.Nat. Rev. Cancer. 2003; 3: 582-591
- Lysophosphatidic acid (LPA) signalling in cell migration and cancer invasion: a focussed review and analysis of LPA receptor gene expression on the basis of more than 1700 cancer microarrays.Biol. Cell. 2013; 105: 317-333
- Lysophosphatidic acid induces migration of human lung-resident mesenchymal stem cells through the beta-catenin pathway.Stem Cells. 2012; 30: 2010-2019
- Two pathways for lysophosphatidic acid production.Biochim. Biophys. Acta. 2008; 1781: 513-518
- Lipoprotein-derived lysophosphatidic acid promotes atherosclerosis by releasing CXCL1 from the endothelium.Cell Metabol. 2011; 13: 592-600
- Phosphatidic acid and lysophosphatidic acid induce haptotactic migration of human monocytes.J. Biol. Chem. 1995; 270: 25549-25556
- LPA receptor signaling: pharmacology, physiology, and pathophysiology.J. Lipid Res. 2014; 55: 1192-1214
- Activatory properties of lysophosphatidic acid on human THP-1 cells.Inflammation. 2007; 30: 167-177
- LPA modulates monocyte migration directly and via LPA-stimulated endothelial cells.Am. J. Physiol. Cell Physiol. 2008; 295: C905-C914
- Lysophosphatidic acid-induced platelet shape change proceeds via Rho/Rho kinase-mediated myosin light-chain and moesin phosphorylation.Cell. Signal. 2000; 12: 645-648
- Mildly oxidized low density lipoprotein rapidly stimulates via activation of the lysophosphatidic acid receptor Src family and Syk tyrosine kinases and Ca2+ influx in human platelets.J. Biol. Chem. 2000; 275: 19159-19166
- Lysophosphatidic acid (LPA) receptors: signaling properties and disease relevance.Prostaglandins Other Lipid Mediat. 2010; 91: 130-138
- Atherosclerotic lesion progression changes lysophosphatidic acid homeostasis to favor its accumulation.Am. J. Pathol. 2010; 176: 3073-3084
- Alpha(1,3)fucosyltransferases FucT-IV and FucT-VII control susceptibility to atherosclerosis in apolipoprotein E-/- mice.Arterioscler. Thromb. Vasc. Biol. 2004; 24: 1897-1903
- Alpha 2,3-sialyltransferase-IV is essential for L-selectin ligand function in inflammation.Eur. J. Immunol. 2006; 36: 3207-3215
- Deletion of core fucosylation on alpha3beta1 integrin down-regulates its functions.J. Biol. Chem. 2006; 281: 38343-38350
- Dysregulation of TGF-beta1 receptor activation leads to abnormal lung development and emphysema-like phenotype in core fucose-deficient mice.Proc. Natl. Acad. Sci. U.S.A. 2005; 102: 15791-15796
- The role of UNC5b in ox-LDL inhibiting migration of RAW264.7 macrophages and the involvement of CCR7.Biochem. Biophys. Res. Commun. 2018; 505: 637-643
- Liver-enriched transcription factors in liver function and development. Part II: the C/EBPs and D site-binding protein in cell cycle control, carcinogenesis, circadian gene regulation, liver regeneration, apoptosis, and liver-specific gene regulation.Pharmacol. Rev. 2004; 56: 291-330
- Tissue-specific transcriptional regulation has diverged significantly between human and mouse.Nat. Genet. 2007; 39: 730-732
- The fucosyltransferase gene family: an amazing summary of the underlying mechanisms of gene evolution.Genetica. 2003; 118: 157-170
- Structural diversity in p160/CREB-binding protein coactivator complexes.J. Biol. Chem. 2006; 281: 14787-14795
- Hepatocyte nuclear factor-1alpha recruits the transcriptional co-activator p300 on the GLUT2 gene promoter.Diabetes. 2002; 51: 1409-1418
- Chitosan oligosaccharides enhance lipid droplets via down-regulation of PCSK9 gene expression in HepG2 cells.Exp. Cell Res. 2018; 366: 152-160
Published online: September 11, 2019
Accepted: September 10, 2019
Received in revised form: August 19, 2019
Received: May 9, 2019
© 2019 Elsevier B.V. All rights reserved.