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.
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
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
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
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.
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.
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
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
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
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
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
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
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
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
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
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.
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.
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.
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
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
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
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
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
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
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
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
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
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.
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
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
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
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
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
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
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
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.
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
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
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
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
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