All Title Author
Keywords Abstract

PLOS ONE  2014 

Human Plasma Lipid Modulation in Schistosomiasis Mansoni Depends on Apolipoprotein E Polymorphism

DOI: 10.1371/journal.pone.0101964

Full-Text   Cite this paper   Add to My Lib

Abstract:

Background Schistosomiasis mansoni is a parasitic liver disease, which causes several metabolic disturbances. Here, we evaluate the influence of Apolipoprotein E (APOE) gene polymorphism, a known modulator of lipid metabolism, on plasma lipid levels in patients with hepatosplenic schistosomiasis. Methodology/Principal Findings Blood samples were used for APOE genotyping and to measure total cholesterol (TC), LDL-C, HDL-C and triglycerides. Schistosomiasis patients had reduced TC, LDL-C and triglycerides (25%, 38% and 32% lower, respectively; P<0.0001) compared to control individuals, whereas HDL-C was increased (10% higher; P = 0.0136). Frequency of the common alleles, ε2, ε3 and ε4, was similar (P = 0.3568) between controls (n = 108) and patients (n = 84), implying that APOE genotype did not affect susceptibility to the advanced stage of schistosomiasis. Nevertheless, while patient TC and LDL-C levels were significantly reduced for each allele (except TC in ε2 patients), changes in HDL-C and triglycerides were noted only for the less common ε2 and ε4 alleles. The most striking finding, however, was that accepted regulation of plasma lipid levels by APOE genotype was disrupted by schistosomiasis. Thus, while ε2 controls had higher TC and LDL-C than ε3 carriers, these parameters were lower in ε2 versus ε3 patients. Similarly, the inverse relationship of TG levels in controls (ε2>ε3>ε4) was absent in patients (ε2 or ε4>ε3), and the increase in HDL-C of ε2 or ε4 patients compared to ε3 patients was not seen in the control groups. Conclusion/Significance We confirm that human schistosomiasis causes dyslipidemia and report for the first time that certain changes in plasma lipid and lipoprotein levels depend on APOE gene polymorphism. Importantly, we also concluded that S. mansoni disrupts the expected regulation of plasma lipids by the different ApoE isoforms. This finding suggests ways to identify new metabolic pathways affected by schistosomiasis and also potential molecular targets to treat associated morbidities.

References

[1]  van der Werf MJ, de Vlas SJ, Brooker S, Looman CW, Nagelkerke NJ, et al. (2003) Quantification of clinical morbidity associated with schistosome infection in sub-Saharan Africa. Acta Trop 86: 125–139. doi: 10.1016/s0001-706x(03)00029-9
[2]  Gryseels B (2012) Schistosomiasis. Infect Dis Clin North Am 26: 383–397. doi: 10.1016/j.idc.2012.03.004
[3]  Leite LA, Pimenta Filho AA, Martins da Fonseca CS, Santana dos Santos B, Ferreira R de C, et al. (2013) Hemostatic dysfunction is increased in patients with hepatosplenic schistosomiasis mansoni and advanced periportal fibrosis. PLoS Negl Trop Dis 7: e2314. doi: 10.1371/journal.pntd.0002314
[4]  Lambertucci JR, Cota GF, Pinto-Silva RA, Serufo JC, Gerspacher-Lara R, et al. (2001) Hepatosplenic schistosomiasis in field-based studies: a combined clinical and sonographic definition. Mem Inst Oswaldo Cruz 96: 147–150. doi: 10.1590/s0074-02762001000900022
[5]  Correia MCB, Domingues ALC, Lacerda HR, Santos EM, Machado CGF, et al. (2009) Platelet function and the von Willebrand factor antigen in the hepatosplenic form of schistosomiasis mansoni. Roy Soc Trop Med Hyg 103: 1053–1058. doi: 10.1016/j.trstmh.2008.11.017
[6]  Ghanem MH, Fahmy MH, Aboul-Kheir F, Mikhail MN, Guirgis FK (1970) Lipid metabolism in bilharzial cirrhosis. Atherosclerosis 12: 55–61. doi: 10.1016/0021-9150(70)90083-3
[7]  Owen JS, Gillett MP (1978) Lecithin:cholesterol acyltransferase deficiency associated with hepatic schistosomiasis mansoni. Scand J Clin Lab Invest Suppl 150: 194–198
[8]  Gillett MP, Sibrian AM, Dimenstein R, Carvalho VC, Gon?alves MM, et al. (1989) Alterations in the fatty acyl composition of plasma cholesteryl esters in Brazilian patients with hepatosplenic schistosomiasis mansoni. Braz J Med Biol Res 22: 949–957.
[9]  Dimenstein R, Carvalho VC, Oliveira DN, Gillett MP (1992) Alterations in the levels and lipid composition of plasma lipoproteins (VLDL, LDL and HDL) in Brazilian patients with hepatosplenic schistosomiasis mansoni. Braz J Med Biol Res 25: 1091–1102.
[10]  Silva CA, Oliveira KF, Carvalho VCO, Domingues ALC, Brandt CT, et al. (2001) Surgical treatment effect on the liver lecithin: cholesterol acyltransferase (LCAT) in schistosomiasis mansoni. Acta Cir Bras 17: 28–30.
[11]  Doenhoff MJ, Stanley RG, Griffiths K, Jackson CJ (2002) An anti-atherogenic effect of Schistosoma mansoni infections in mice associated with a parasite-induced lowering of blood total cholesterol. Parasitology 125: 415–421. doi: 10.1017/s0031182002002275
[12]  La Flamme AC, Harvie M, Kenwright D, Cameron K, Rawlence N, et al. (2007) Chronic exposure to schistosome eggs reduces serum cholesterol but has no effect on atherosclerotic lesion development. Parasite Immunol 29: 259–266. doi: 10.1111/j.1365-3024.2007.00942.x
[13]  Lima VLM, Sena VLM, Stewart B, Owen JS, Dolphin PJ (1998) An evaluation of the marmoset Callithrix jacchus (sagüi) as an experimental model for the dyslipoproteinemia of human Schistosomiasis mansoni. Biochim Biophys Acta 1393: 235–243. doi: 10.1016/s0005-2760(98)00076-9
[14]  Ramos TMB, Vasconcelos AS, Carvalho VC, Lima VLM (2004) Alterations in cholesterol, triglyceride and total phospholipid levels in plasma of Callithrix jacchus (sagüi) reinfected by Schistosoma mansoni. Rev Soc Bras Med Trop 37: 37–40. doi: 10.1590/s0037-86822004000100010
[15]  Mahley RW, Weisgraber KH, Huang Y (2009) Apolipoprotein E: structure determines function, from atherosclerosis to Alzheimer's disease to AIDS. J Lipid Res 50: S183–S188. doi: 10.1194/jlr.r800069-jlr200
[16]  Papaioannou I, Simons JP, Owen JS (2012) Targeted in situ gene correction of dysfunctional APOE alleles to produce atheroprotective plasma ApoE3 protein. Cardiol Res Pract 2012: 1–16. doi: 10.1155/2012/148796
[17]  Li H, Dhanasekaran P, Alexander ET, Rader DJ, Phillips MC, et al. (2013) Molecular mechanisms responsible for the differential effects of apoE3 and apoE4 on plasma lipoprotein-cholesterol levels. Arterioscler Thromb Vasc Biol 33: 687–693. doi: 10.1161/atvbaha.112.301193
[18]  Mahley RW, Huang Y, Rall AC Jr (1999) Pathogenesis of type III hyperlipoproteinemia (dysbetalipoproteinemia). Questions, quandaries, and paradoxes. J Lipid Res 40: 1933–1949.
[19]  Harris JD, Evans V, Owen JS (2006) ApoE gene therapy to treat hyperlipidemia and atherosclerosis. Curr Opin Mol Ther 8: 275–287.
[20]  Getz GS, Reardon CA (2009) Apoprotein E as a lipid transport and signaling protein in the blood, liver, and artery wall. J Lipid Res 50: S156–S161. doi: 10.1194/jlr.r800058-jlr200
[21]  Zhang KJ, Zhang HL, Zhang XM, Zheng XY, Quezada HC, Zhang D, et al. (2011) Apolipoprotein E isoform-specific effects on cytokine and nitric oxide production from mouse Schwann cells after inflammatory stimulation. Neurosci Lett 499: 175–180. doi: 10.1016/j.neulet.2011.05.050
[22]  Zhang H, Wu LM, Wu J (2011) Cross-talk between apolipoprotein E and cytokines. Mediators Inflamm 2011: 949072. doi: 10.1155/2011/949072
[23]  Wozniak MA, Faragher EB, Todd JA, Koram KA, Riley EM, et al. (2003) Does apolipoprotein E polymorphism influence susceptibility to malaria? J Med Genet 40: 348–351. doi: 10.1136/jmg.40.5.348
[24]  Tursen U, Kaya TI, Eskandari G, Bocekli E, Muslu N, et al. (2004) Apolipoprotein E gene polymorphism and serum lipids in patients with superficial fungal disease. Yonsei Med J 45: 375–379.
[25]  Burt TD, Agan BK, Marconi VC, He W, Kulkarni H, et al. (2008) Apolipoprotein (apo) E4 enhances HIV-1 cell entry in vitro, and the APOE epsilon4/epsilon4 genotype accelerates HIV disease progression. Proc Natl Acad Sci U S A 105: 8718–8723. doi: 10.1073/pnas.0803526105
[26]  Wozniak MA, Itzhaki RF, Faragher EB, James MW, Ryder SD, et al. (2002) Apolipoprotein E-ε4 protects against severe liver disease caused by hepatitis C virus. Hepatology 36: 456–463. doi: 10.1053/jhep.2002.34745
[27]  Niamey Working Group. (2000) Ultrasound in schistosomiasis: a practical guide to the standardized use of ultrasonography for the assessment of schistosomiasis-related morbidity. Geneva: World Health Organization. TDR/STR/SCH/00.1. Available: http://apps.who.int/iris/bitstream/10665?/66535/1/TDR_STR_SCH_00.1.pdf.
[28]  Gidez LI, Miller GJ, Burstein M, Slagle S, Eder HA (1982) Separation and quantitation of subclasses of human plasma high density lipoproteins by a simple precipitation procedure. J Lipid Res 23: 1206–1223.
[29]  Dos Santos BS, Melo Junior MR, Paiva MHS, Pimenta Filho AA, Araujo TF, et al. (2009) Comparative analysis of lipid profile in men from Pernambuco State, according to III and IV Brazilian Dyslipidemias Guidelines. Rev Bras Anal Clin 41(4): 295–297.
[30]  Miller SA, Dykes DD, Polesky HF (1988) A simple salting out procedure for extracting DNA from human nucleated cells. Nucl Acids Res 16: 1215. doi: 10.1093/nar/16.3.1215
[31]  Kim SW, Heo JH, Kim CH, Yoo DC, Won DH, et al. (2010) Rapid and direct detection of apolipoprotein E genotypes using whole blood from humans. J Toxicol Environ Health A 73: 1502–1510. doi: 10.1080/15287394.2010.511573
[32]  Mendes-Lana A, Pena GG, Freitas SN, Lima AA, Nicolato RL, et al. (2007) Apolipoprotein E polymorphism in Brazilian dyslipidemic individuals: Ouro Preto study. Braz J Med Biol Res 40: 49–56. doi: 10.1590/s0100-879x2007000100007
[33]  Fuzikawa AK, Peixoto SV, Taufer M, Moriguchi EH, Lima-Costa MF (2008) Association of ApoE polymorphisms with prevalent hypertension in 1406 older adults: the Bambuí Health Aging Study (BHAS). Braz J Med Biol Res 41: 89–94. doi: 10.1590/s0100-879x2008000200002
[34]  Alvim RO, Freitas SR, Ferreira NE, Santos PC, Cunha RS, et al. (2010) APOE polymorphism is associated with lipid profile, but not with arterial stiffness in the general population. Lipids Health Dis 9: 128. doi: 10.1186/1476-511x-9-128
[35]  Price DA, Bassendine MF, Norris SM, Golding C, Toms GL, et al. (2006) Apolipoprotein ε3 allele is associated with persistent hepatitis C virus infection. Gut 55: 715–718. doi: 10.1136/gut.2005.079905
[36]  Ahn SJ, Kim DK, Kim SS, Bae CB, Cho HJ, et al. (2012) Association between apolipoprotein E genotype, chronic liver disease, and hepatitis B virus. Clin Mol Hepatol 18: 295–301. doi: 10.3350/cmh.2012.18.3.295
[37]  Fabris C, Vandelli C, Toniutto P, Minisini R, Colletta C, et al. (2011) Apolipoprotein E genotypes modulate fibrosis progression in patients with chronic hepatitis C and persistently normal transaminases. J Gastroenterol Hepatol 26: 328–333. doi: 10.1111/j.1440-1746.2010.06403.x
[38]  Marquet S, Abel L, Hillaire D, Dessein H, Kalil J, et al. (1996) Genetic localization of a locus controlling the intensity of infection by Schistosoma mansoni on chromosome 5q31–q33. Nat Genet 14: 181–184. doi: 10.1038/ng1096-181
[39]  Dessein AJ, Hillaire D, Elwali NE, Marquet S, Mohamed-Ali Q, et al. (1999) Severe hepatic fibrosis in Schistosoma mansoni infection is controlled by a major locus that is closely linked to the interferon-gamma receptor gene. Am J Hum Genet 65: 709–721. doi: 10.1086/302526
[40]  Dessein A, Arnaud V, He H, Li J, Dessein H, et al. (2013) Genetic analysis of human predisposition to hepatosplenic disease caused by schistosomes reveals the crucial role of connective tissue growth factor in rapid progression to severe hepatic fibrosis. Pathol Biol (Paris) 61: 3–10. doi: 10.1016/j.patbio.2013.01.005
[41]  Stanley RG, Jackson CL, Griffiths K, Doenhoff MJ (2009) Effects of Schistosoma mansoni worms and eggs on circulating cholesterol and liver lipids in mice. Atherosclerosis 207: 131–138. doi: 10.1016/j.atherosclerosis.2009.04.037
[42]  Brandt CT, Godoi ET, Valen?a A, Mascena GV, Godoi JT (2013) Atherogenesis: diseases that may affect the natural history “schistosomiasis and HIV infection”. In: Rezzani R, editor. Current Trends in Atherogenesis. InTech Europe, Croatia. pp. 81–96.
[43]  Tempone AJ, Bianconi ML, Rumjanek FD (1997) The interaction of human LDL with the tegument of adult Schistosoma mansoni. Mol Cell Biochem 177: 139–144.
[44]  Sprong H, Suchanek M, van Dijk SM, van Remoortere A, Klumperman J, et al. (2006) Aberrant receptor-mediated endocytosis of Schistosoma mansoni glycoproteins on host lipoproteins. PLos Med 3: 1360–1370. doi: 10.1371/journal.pmed.0030253
[45]  Agellon LB, Walsh A, Hayek T, Moulin P, Jiang XC, et al. (1991) Reduced high density lipoprotein cholesterol in human cholesteryl ester transfer protein transgenic mice. J Biol Chem 266: 10796–10801. doi: 10.1172/jci115887
[46]  Powell-Braxton L, Véniant M, Latvala RD, Hirano KI, Won WB, et al. (1998) A mouse model of human familial hypercholesterolemia: markedly elevated low density lipoprotein cholesterol levels and severe atherosclerosis on a low-fat chow diet. Nat Med 4: 934–938. doi: 10.1038/nm0898-934
[47]  Khovidhunkit W, Kim M-S, Memon RA, Shigenaga JK, Moser AH, et al. (2004) Effects of infection and inflammation on lipid and lipoprotein metabolism: mechanisms and consequences to the host. J Lipid Res 45: 1169–1196. doi: 10.1194/jlr.r300019-jlr200
[48]  Haas MJ, Mooradian AD (2010) Regulation of high-density lipoprotein by inflammatory cytokines: establishing links between immune dysfunction and cardiovascular disease. Diabetes Metab Res Rev 26: 90–99. doi: 10.1002/dmrr.1057
[49]  G HB, Rao VS, Kakkar VV (2011) Friend turns foe: transformation of anti-inflammatory HDL to proinflammatory HDL during acute-phase response. Cholesterol 2011: 274629. doi: 10.1155/2011/274629
[50]  Pruzanski W, Stefanski E, de Beer FC, de Beer MC, Ravandi A, et al. (2000) Comparative analysis of lipid composition of normal and acute-phase high density lipoproteins. J Lipid Res 41: 1035–1047.
[51]  Natarajan P, Ray KK, Cannon CP (2010) High-density lipoprotein and coronary heart disease: current and future therapies. J Am Coll Cardiol 55: 1283–1299. doi: 10.1016/j.jacc.2010.01.008
[52]  Van Lenten BJ, Hama SY, de Beer FC, Stafforini DM, McIntyre TM, et al. (1995) Anti-inflammatory HDL becomes pro-inflammatory during the acute phase response. Loss of protective effect of HDL against LDL oxidation in aortic wall cell cocultures. J Clin Invest 96: 2758–2767. doi: 10.1172/jci118345
[53]  Saemann MD, Poglitsch M, Kopecky C, Haidinger M, Horl WH, et al. (2010) The versatility of HDL: a crucial anti-inflammatory regulator. Eur J Clin Invest 40: 1131–1143. doi: 10.1111/j.1365-2362.2010.02361.x
[54]  Feingold KR, Grunfeld C (2010) The acute phase response inhibits reverse cholesterol transport. J Lipid Res 51: 682–684. doi: 10.1194/jlr.e005454
[55]  Facundo HTF, Brandt CT, Owen JS, Lima VLM (2004) Elevated levels of erythrocyte conjugated dienes indicate increased lipid peroxidation in schistosomiasis mansoni patients. Braz J Med Biol Res 37: 957–962. doi: 10.1590/s0100-879x2004000700003
[56]  Bennet AM, Di Angelantonio E, Ye Z, Wensley F, Dahlin A, et al. (2007) Association of apolipoprotein E genotypes with lipid levels and coronary risk. JAMA 298: 1300–1311. doi: 10.1001/jama.298.11.1300
[57]  Krimbou L, Tremblay M, Davignon J, Cohn JS (1997) Characterization of human plasma apolipoprotein E-containing lipoproteins in the high density lipoprotein size range: focus on pre-β1-LpE, pre-β2-LpE, and α-LpE. J Lipid Res 38: 35–48.
[58]  Huang Y, von Eckardstein A, Wu S, Assmann G (1995) Effects of the apolipoprotein E polymorphism on uptake and transfer of cell-derived cholesterol in plasma. J Clin Invest 96: 2693–2701. doi: 10.1172/jci118336
[59]  Chen CH, Albers JJ (1985) Activation of lecithin: cholesterol acyltransferase by apolipoproteins E-2, E-3, and A-IV isolated from human plasma. Biochim Biophys Acta 836: 279–285. doi: 10.1016/0005-2760(85)90131-6
[60]  Cassel DL, Phillips MC, Rostron P, Rothblat GH, Utermann G (1984) The conformation of apolipoprotein E isoforms in phospholipid complexes and their interaction with human Hep G2 cells. Atherosclerosis 52: 203–218. doi: 10.1016/0021-9150(84)90119-9
[61]  Hirata H, Yimin, Segawa S, Ozaki M, Kobayashi N, et al. (2012) Xanthohumol prevents atherosclerosis by reducing arterial cholesterol content via CETP and Apolipoprotein E in CETP-transgenic mice. PLoS ONE 7: e49415. doi: 10.1371/journal.pone.0049415
[62]  Steinmetz A, Jakobs C, Motzny S, Kaffarnik H (1989) Differential distribution of apolipoprotein E isoforms in human plasma lipoproteins. Arteriosclerosis 9: 405–411. doi: 10.1161/01.atv.9.3.405
[63]  Mahley RW, Huang Y, Weisgraber KH (2006) Putting cholesterol in its place: apoE and reverse cholesterol transport. J Clin Invest 116: 1226–1229. doi: 10.1172/jci28632
[64]  Miyata M, Smith JD (1996) Apolipoprotein E allele-specific antioxidant activity and effects on cytotoxicity by oxidative insults and β-amyloids peptides. Nat Genet 14: 55–61. doi: 10.1038/ng0996-55
[65]  de Oliveira RB, Senger MR, Vasques LM, Gasparotto J, dos Santos JP, et al. (2013) Schistosoma mansoni infection causes oxidative stress and alters receptor for advanced glycation endproduct (RAGE) and tau levels in multiple organs in mice. Int J Parasitol 43: 371–379. doi: 10.1016/j.ijpara.2012.12.006
[66]  Iannello S, Cavaleri A, Camuto M, Pisano MG, Milazzo P (2002) Low fasting serum triglyceride and high free fatty acid levels in pulmonary fibrosis: a previously unreported finding. MedGenMed 4: 5.
[67]  Harvie M, Jordan TW, La Flamme AC (2007) Differential liver protein expression during schistosomiasis. Infect Immun 75: 736–744. doi: 10.1128/iai.01048-06
[68]  el-Marzouki ZM, Amin AM (1997) Changes in serum lipids of mice experimentally infected with Schistosoma mansoni. J Egypt Soc Parasitol 27: 419–429.
[69]  Dallongeville J, Lussier-Cacan S, Davignon J (1992) Modulation of plasma triglyceride levels by apoE phenotype: a meta-analysis. J Lipid Res 33: 447–454.
[70]  Khan TA, Shah T, Prieto D, Zhang W, Price J, et al. (2013) Apolipoprotein E genotype, cardiovascular biomarkers and risk of stroke: systematic review and meta-analysis of 14,015 stroke cases and pooled analysis of primary biomarker data from up to 60,883 individuals. Int J Epidemiol. 42: 475–492. doi: 10.1093/ije/dyt034
[71]  Heeren J, Beisiegel U, Grewal T (2006) Apolipoprotein E recycling implications for dyslipidemia and atherosclerosis. Arterioscler Thromb Vasc Biol 26: 442–448.
[72]  Almeida S, Fiegenbaum M, Andrade FM, Osório-Wender MC, Hutz MH (2006) ESR1 and APOE gene polymorphisms, serum lipids, and hormonal replacement therapy. Maturitas 54: 119–126. doi: 10.1016/j.maturitas.2005.09.009

Full-Text

comments powered by Disqus