Negative Correlation Between Serum Levels of Homocysteine and Apolipoprotein M

Author(s): J. Wei, Y. Yu, Y. Feng, J. Zhang, Q. Jiang, L. Zheng, X. Zhang, N. Xu, G. Luo*.

Journal Name: Current Molecular Medicine

Volume 19 , Issue 2 , 2019

  Journal Home
Translate in Chinese
Submit Manuscript
Submit Proposal


Background: Homocysteine (Hcy) has been suggested as an independent risk factor for atherosclerosis. Apolipoprotein M (apoM) is a constituent of the HDL particles. The goal of this study was to examine the serum levels of homocysteine and apoM and to determine whether homocysteine influences apoM synthesis.

Methods: Serum levels of apoM and Hcy in 17 hyperhomocysteinemia (HHcy) patients and 19 controls were measured and their correlations were analyzed. Different concentrations of homocysteine (Hcy) and LY294002, a specific phosphoinositide 3- kinase (PI3K) inhibitor, were used to treat HepG2 cells. The mRNA levels were determined by RT-PCR and the apoM protein mass was measured by western blot.

Results: We found that decreased serum apoM levels corresponded with serum HDL levels in HHcy patients, while the serum apoM levels showed a statistically significant negative correlation with the serum Hcy levels. Moreover, apoM mRNA and protein levels were significantly decreased after the administration of Hcy in HepG2 cells, and this effect could be abolished by addition of LY294002.

Conclusions: Present study demonstrates that Hcy downregulates the expression of apoM by mechanisms involving the PI3K signal pathway.

Keywords: Homocysteine, apolipoprotein M, lipid metabolism, PI3K, hyperhomocysteinemia, cardiovascular diseases.

Mudd SH, Finkelstein JD, Refsum H, et al. Homocysteine and its disulfide derivatives: a suggested consensus terminology. Arterioscler Thromb Vasc Biol 2000; 20(7): 1704-6.
Jansen M, Dannhardt G. Antagonists and agonists at the glycine site of the NMDA receptor for therapeutic interventions. Eur J Med Chem 2003; 38(7-8): 661-70.
Mudd SH, Finkelstein JD, Irreverre F, et al. Homocystinuria: An Enzymatic Defect. Science 1964; 143(3613): 1443-5.
Frosst P, Blom HJ, Milos R, et al. A candidate genetic risk factor for vascular disease: A common mutation in methylenetetrahydrofolate reductase. Nat Genet 1995; 10(1): 111-3.
Curro M, Gugliandolo A, Gangemi C, et al. Toxic effects of mildly elevated homocysteine concentrations in neuronal-like cells. Neurochem Res 2014; 39(8): 1485-95.
Ueland PM, Refsum H. Plasma homocysteine, a risk factor for vascular disease: Plasma levels in health, disease, and drug therapy. J Lab Clin Med 1989; 114(5): 473-501.
Abushik PA, Niittykoski M, Giniatullina R, et al. The role of NMDA and mGluR5 receptors in calcium mobilization and neurotoxicity of homocysteine in trigeminal and cortical neurons and glial cells. J Neurochem 2014; 129(2): 264-74.
Qureshi I, Chen H, Brown AT, et al. Homocysteine-induced vascular dysregulation is mediated by the NMDA receptor. Vasc Med 2005; 10(3): 215-23.
Clarke R, Daly L, Robinson K, et al. Hyperhomocysteinemia: an independent risk factor for vascular disease. N Engl J Med 1991; 324(17): 1149-55.
Veeranna V, Zalawadiya SK, Niraj A, et al. Homocysteine and reclassification of cardiovascular disease risk. J Am Coll Cardiol 2011; 58(10): 1025-33.
Lai WK, Kan MY. Homocysteine-Induced Endothelial Dysfunction. Ann Nutr Metab 2015; 67(1): 1-12.
Chiang JK, Sung ML, Yu HR, et al. Homocysteine induces smooth muscle cell proliferation through differential regulation of cyclins A and D1 expression. J Cell Physiol 2011; 226(4): 1017-26.
Weiss N, Heydrick SJ, Postea O, et al. Influence of hyperhomocysteinemia on the cellular redox state--impact on homocysteine-induced endothelial dysfunction. Clin Chem Lab Med 2003; 41(11): 1455-61.
Wu S, Gao X, Yang S, et al. The role of endoplasmic reticulum stress in endothelial dysfunction induced by homocysteine thiolactone. Fundam Clin Pharmacol 2015; 29(3): 252-9.
Liao D, Tan H, Hui R, et al. Hyperhomocysteinemia decreases circulating high-density lipoprotein by inhibiting apolipoprotein A-I Protein synthesis and enhancing HDL cholesterol clearance. Circ Res 2006; 99(6): 598-606.
Wang Y, Liu J, Jiang Y, et al. Hyperhomocysteinemia is associated with decreased apolipoprotein AI levels in normal healthy people. BMC Cardiovasc Disord 2016; 16(1): 10.
Holven KB, Aukrust P, Retterstol K, et al. The antiatherogenic function of HDL is impaired in hyperhomocysteinemic subjects. J Nutr 2008; 138(11): 2070-5.
Rader DJ, Hovingh GK. HDL and cardiovascular disease. Lancet 2014; 384(9943): 618-25.
Wolfrum C, Poy MN, Stoffel M. Apolipoprotein M is required for prebeta-HDL formation and cholesterol efflux to HDL and protects against atherosclerosis. Nat Med 2005; 11(4): 418-22.
Christoffersen C, Jauhiainen M, Moser M, et al. Effect of apolipoprotein M on high density lipoprotein metabolism and atherosclerosis in low density lipoprotein receptor knock-out mice. J Biol Chem 2008; 283(4): 1839-47.
Elsoe S, Ahnstrom J, Christoffersen C, et al. Apolipoprotein M binds oxidized phospholipids and increases the antioxidant effect of HDL. Atherosclerosis 2012; 221(1): 91-7.
Christoffersen C, Obinata H, Kumaraswamy SB, et al. Endothelium-protective sphingosine-1-phosphate provided by HDL-associated apolipoprotein M. Proc Natl Acad Sci USA 2011; 108(23): 9613-8.
Murata N, Sato K, Kon J, et al. Interaction of sphingosine 1-phosphate with plasma components, including lipoproteins, regulates the lipid receptor-mediated actions. Biochem J 2000; 352(Pt 3): 809-15.
Galvani S, Sanson M, Blaho VA, et al. HDL-bound sphingosine 1-phosphate acts as a biased agonist for the endothelial cell receptor S1P1 to limit vascular inflammation. Sci Signal 2015; 8(389): ra79.
Wei J, Yu Y, Luo GH, et al. 17beta-estradiol regulates the expression of apolipoprotein M through estrogen receptor alpha-specific binding motif in its promoter. Lipids Health Dis 2017; 16(1): 66.
Wei J, Shi Y, Zhang X, et al. Estrogen upregulates hepatic apolipoprotein M expression via the estrogen receptor. Biochim Biophys Acta 2011; 1811(12): 1146-51.
Lentz SR. Mechanisms of homocysteine-induced atherothrombosis. J Thromb Haemost 2005; 3(8): 1646-54.
Boushey CJ, Beresford SAA, Omenn GS, et al. A meta-analysis of plasma homocysteine as a risk factor for arteriosclerotic vascular disease and the potential preventive role of folic acid In homocysteine metabolism: from basic science to clinical medicine. Edited by Graham I, Refsum H,Rosenberg IH, Ueland PM, Shuman JM.. Boston, MA: Springer US 1997; pp. 245-9.
McCully KS. Homocysteine and the pathogenesis of atherosclerosis. Expert Rev Clin Pharmacol 2015; 8(2): 211-9.
Mikael LG, Genest JJR, Rozen R. Elevated homocysteine reduces apolipoprotein A-I expression in hyperhomocysteinemic mice and in males with coronary artery disease. Circ Res 2006; 98(4): 564-71.
Jin P, Bian Y, Wang K, et al. Homocysteine accelerates atherosclerosis via inhibiting LXRalpha-mediated ABCA1/ABCG1-dependent cholesterol efflux from macrophages. Life Sci 2018; 214: 41-50.
Downes CP, Leslie NR, Batty IH, et al. Metabolic switching of PI3K-dependent lipid signals. Biochem Soc Trans 2007; 35(Pt 2): 188-92.
Ricoult SJ, Yecies JL, Ben-Sahra I, et al. Oncogenic PI3K and K-Ras stimulate de novo lipid synthesis through mTORC1 and SREBP. Oncogene 2016; 35(10): 1250-60.
Shastry S, James LR. Homocysteine-induced macrophage inflammatory protein-2 production by glomerular mesangial cells is mediated by PI3 Kinase and p38 MAPK. J Inflamm (Lond) 2009; 6: 27.
Xu N, Ahren B, Jiang J, et al. Down-regulation of apolipoprotein M expression is mediated by phosphatidylinositol 3-kinase in HepG2 cells. Biochim Biophys Acta 2006; 1761(2): 256-60.

Rights & PermissionsPrintExport Cite as

Article Details

Year: 2019
Page: [120 - 126]
Pages: 7
DOI: 10.2174/1566524019666190308115624
Price: $58

Article Metrics

PDF: 36
PRC: 1