Complement Components, C3 and C4, and the Metabolic Syndrome

Author(s): Melanie Copenhaver, Chack-Yung Yu, Robert P. Hoffman*.

Journal Name: Current Diabetes Reviews

Volume 15 , Issue 1 , 2019

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Abstract:

Introduction: Increased systemic inflammation plays a significant role in the development of adult cardiometabolic diseases such as insulin resistance, dyslipidemia, atherosclerosis, and hypertension. The complement system is a part of the innate immune system and plays a key role in the regulation of inflammation. Of particular importance is the activation of complement components C3 and C4. C3 is produced primarily by the liver but is also produced in adipocytes, macrophages and endothelial cells, all of which are present in adipose tissues. Dietary fat and chylomicrons stimulate C3 production. Adipocytes in addition to producing C3 also have receptors for activated C3 and other complement components and thus also respond to as well as produce a target for complement. C3adesArg, also known as acylation stimulation factor, increases adipocyte triglyceride synthesis and release. These physiological effects play a significant role in the development of metabolic syndrome. Epidemiologically, obese adults and non-obese adults with cardiometabolic disease who are not obese have been shown to have increased complement levels. C4 levels also correlate with body mass index. Genetically, specific C3 polymorphisms have been shown to predict future cardiovascular events and. D decreased C4 long gene copy number is associated with increased longevity.

Conclusion: Future research is clearly needed to clarify the role of complement in the development of cardiovascular disease and mechanisms for its action. The complement system may provide a new area for intervention in the prevention of cardiometabolic diseases.

Keywords: Complement, metabolic syndrome, inflammation, adipose, obesity, insulin resistance.

[1]
Ahmad I, Zhan M, Miller M. High prevalence of C-reactive protein elevation with normal triglycerides (100-149 mg/dL): are triglyceride levels below 100 mg/dL more optimal in coronary heart disease risk assessment? Am J Med Sci 2005; 329: 173-7.
[2]
Albert MA, Glynn RJ, Buring J, Ridker PM. C-reactive protein levels among women of various ethnic groups living in the United States (from the Women’s Health Study). Am J Cardiol 2004; 93: 1238-42.
[3]
Dali-Youcef N, Mecili M, Ricci R, Andres E. Metabolic inflammation: connecting obesity and insulin resistance. Ann Med 2013; 45: 242-53.
[4]
den Engelsen C, Koekkoek PS, Gorter KJ, van den Donk M, Salome PL, Rutten GE. High-sensitivity C-reactive protein to detect metabolic syndrome in a centrally obese population: a cross-sectional analysis. Cardiovasc Diabetol 2012; 11: 25.
[5]
Albert MA, Glynn RJ, Ridker PM. Effect of physical activity on serum C-reactive protein. J Cardiol 2004; 93: 221-5.
[6]
Albert MA, Ridker PM. Inflammatory biomarkers in African Americans: A potential link to accelerated atherosclerosis. Rev Cardiovasc Med 2004; 5(Suppl. 3): S22-7.
[7]
Carlsson AC, Ostgren CJ, Nystrom FH, et al. Association of soluble tumor necrosis factor receptors 1 and 2 with nephropathy, cardiovascular events, and total mortality in type 2 diabetes. Cardiovasc Diabetol 2016; 15: 40.
[8]
Lee S, Kim IT, Park HB, et al. High-sensitivity C-reactive protein can predict major adverse cardiovascular events in Korean patients with type 2 diabetes. J Korean Med Sci 2011; 26: 1322-7.
[9]
Mohlenkamp S, Lehmann N, Moebus S, et al. Quantification of coronary atherosclerosis and inflammation to predict coronary events and all-cause mortality. J Am Coll Cardiol 2011; 57: 1455-64.
[10]
Tayefi M, Tajfard M, Saffar S, et al. hs-CRP is strongly associated with coronary heart disease (CHD): A data mining approach using decision tree algorithm. Comput Methods Programs Biomed 2017; 141: 105-9.
[11]
Ricklin D, Reis ES, Lambris JD. Complement in disease: A defence system turning offensive. Nat Rev Nephrol 2016; 12: 383-401.
[12]
Koistinen HA, Koivisto VA, Ebeling P. Serum complement protein C3 concentration is elevated in insulin resistance in obese men. Eur J Intern Med 2000; 11: 21-6.
[13]
Ghebrehiwet B. The complement system: An evolution in progress. F1000 Res 2016; 5: 2840.
[14]
Barnum SR. Complement: A primer for the coming therapeutic revolution. Pharmacol Ther 2017; 172: 63-72.
[15]
Noris M, Remuzzi G. Overview of complement activation and regulation.In: Seminars in nephrology; 2013. Elsevier 2013; pp. 479-92.
[16]
Janeway Jr CA Jr, Travers P, Walport M, Shlomchik MJ. The complement system and innate immunity. In: Immunobiology: The Immune System in Health and Disease 5th ed. 2001.
[17]
Ricklin D, Lambris JD. Complement in immune and inflammatory disorders: pathophysiological mechanisms. J Immunol 2013; 190: 3831-8.
[18]
Lupu F, Keshari RS, Lambris JD, Coggeshall KM. Crosstalk between the coagulation and complement systems in sepsis. Thromb Res 2014; 133(Suppl. 1): S28-31.
[19]
Hertle E, Stehouwer CD, van Greevenbroek MM. The complement system in human cardiometabolic disease. Mol Immunol 2014; 61: 135-48.
[20]
Barbu A, Hamad OA, Lind L, Ekdahl KN, Nilsson B. The role of complement factor C3 in lipid metabolism. Mol Immunol 2015; 67: 101-7.
[21]
Onat A, Can G, Rezvani R, Cianflone K. Complement C3 and cleavage products in cardiometabolic risk. Clin Chim Acta 2011; 412: 1171-9.
[22]
Nilsson B, Hamad OA, Ahlstrom H, et al. C3 and C4 are strongly related to adipose tissue variables and cardiovascular risk factors. Eur J Clin Invest 2014; 44: 587-96.
[23]
Hertle E, Stehouwer C, van Greevenbroek M. The complement system in human cardiometabolic disease. Mol Immunol 2014; 61: 135-48.
[24]
Baldo A, Sniderman AD, St-Luce S, et al. The adipsin-acylation stimulating protein system and regulation of intracellular triglyceride synthesis. J Clin Invest 1993; 92: 1543-7.
[25]
Yasruel Z, Cianflone K, Sniderman AD, Rosenbloom M, Walsh M, Rodriguez MA. Effect of acylation stimulating protein on the triacylglycerol synthetic pathway of human adipose tissue. Lipids 1991; 26: 495-9.
[26]
Hoffman RP. Metabolic syndrome racial differences in adolescents. Curr Diabetes Rev 2009; 5: 259-65.
[27]
Jonkers IJAM, van de Ree MA, Smelt AHM, et al. Insulin resistance but not hypertriglyceridemia per se is associated with endothelial dysfunction in chronic hypertriglyceridemia. Cardiovasc Res 2002; 53: 496-501.
[28]
Lteif AA, Han K, Mather KJ. Obesity, insulin resistance, and the metabolic syndrome: Determinants of endothelial dysfunction in whites and blacks. Circulation 2005; 112: 32-8.
[29]
Barbu A, Hamad OA, Lind L, Ekdahl KN, Nilsson B. The role of complement factor C3 in lipid metabolism. Mol Immunol 2015; 67: 101-7.
[30]
Ajjan R, Carter AM, Somani R, Kain K, Grant PJ. Ethnic differences in cardiovascular risk factors in healthy Caucasian and South Asian individuals with the metabolic syndrome. J Thromb Haemost 2007; 5: 754-60.
[31]
Ajjan R, Grant PJ, Futers TS, et al. Complement C3 and C-reactive protein levels in patients with stable coronary artery disease. Thromb Haemost 2005; 94: 1048-53.
[32]
Hernandez-Mijares A, Banuls C, Bellod L, et al. Effect of weight loss on C3 and C4 components of complement in obese patients. Eur J Clin Invest 2012; 42: 503-9.
[33]
Koistinen HA, Koivisto VA, Ebeling P. Serum complement C3 concentration is elevated in in insulin resistant obese men. Eur J Intern Med 2000; 11: 21-6.
[34]
Ohsawa I, Inoshita H, Ishii M, et al. Metabolic impact on serum levels of complement component 3 in Japanese patients. J Clin Lab Anal 2010; 24: 113-8.
[35]
Onat A, Uzunlar B, Hergenc G, et al. Cross-sectional study of complement C3 as a coronary risk factor among men and women. Clin Sci 2005; 108: 129-35.
[36]
Phillips CM, Kesse-Guyot E, Ahluwalia N, et al. Dietary fat, abdominal obesity and smoking modulate the relationship between plasma complement component 3 concentrations and metabolic syndrome risk. Atherosclerosis 2012; 220: 513-9.
[37]
Onat A, Hergenc G, Can G, Kaya Z, Yuksel H. Serum complement C3: a determinant of cardiometabolic risk, additive to the metabolic syndrome, in middle-aged population. Metabolism 2010; 59: 628-34.
[38]
van Oostrom AJ, Alipour A, Plokker TW, Sniderman AD, Cabezas MC. The metabolic syndrome in relation to complement component 3 and postprandial lipemia in patients from an outpatient lipid clinic and healthy volunteers. Atherosclerosis 2007; 190: 167-73.
[39]
Vidigal Fde C, Ribeiro AQ, Babio N, Salas-Salvado J, Bressan J. Prevalence of metabolic syndrome and pre-metabolic syndrome in health professionals: LATINMETS Brazil study. Diabetol Metab Syndr 2015; 7: 6.
[40]
Koistinen HA, Vidal H, Karonen SL, et al. Plasma acylation stimulating protein concentration and subcutaneous adipose tissue C3 mRNA expression in nondiabetic and type 2 diabetic men. Arterioscler Thromb Vasc Biol 2001; 21: 1034-9.
[41]
Muscari A, Bozzoli C, Puddu GM, et al. Association of serum C3 levels with the risk of myocardial infarction. Am J Med 1995; 98: 357-64.
[42]
Wamba PC, Mi J, Zhao XY, et al. Acylation stimulating protein but not complement C3 associates with metabolic syndrome components in Chinese children and adolescents. Eur J Endocrinol 2008; 159: 781-90.
[43]
Wei JN, Li HY, Sung FC, et al. Obesity and clustering of cardiovascular disease risk factors are associated with elevated plasma complement C3 in children and adolescents. Pediatr Diabetes 2012; 13: 476-83.
[44]
Botto M, Fong KY, So AK, Koch C, Walport MJ. Molecular basis of polymorphisms of human complement component C3. J Exp Med 1990; 172: 1011-7.
[45]
Phillips CM, Goumidi L, Bertrais S, et al. Complement component 3 polymorphisms interact with polyunsaturated fatty acids to modulate risk of metabolic syndrome. Am J Clin Nutr 2009; 90: 1665-73.
[46]
Ajjan RA, Grant PJ, Futers TS, Brown JM, Carter AM. The association of complement C3 genotype with coronary artery disease, markers of the metabolic syndrome and C3 plasma levels. Thromb Haemost 2006; 95: 393-4.
[47]
Chung EK, Wu YL, Yang Y, Zhou B, Yu CY. Human complement components C4A and C4B genetic diversities: Complex genotypes and phenotypes. In: Curr Protoc Immunol 2005; Chapter 13: Unit 13 8. 2005.
[48]
Chung EK, Yang Y, Rupert KL, et al. Determining the one, two, three, or four long and short loci of human complement C4 in a major histocompatibility complex haplotype encoding C4A or C4B proteins. Am J Hum Genet 2002; 71: 810-22.
[49]
Margery-Muir AA, Wetherall JD, Castley AS, et al. Establishment of gene copy number-specific normal ranges for serum C4 and its utility for interpretation in patients with chronically low serum C4 concentrations. Arthritis Rheumatol 2014; 66: 2512-20.
[50]
Saxena K, Kitzmiller KJ, Wu YL, et al. Great genotypic and phenotypic diversities associated with copy-number variations of complement C4 and RP-C4-CYP21-TNX (RCCX) modules: a comparison of Asian-Indian and European American populations. Mol Immunol 2009; 46: 1289-303.
[51]
Yang Y, Chung EK, Zhou B, et al. Diversity in intrinsic strengths of the human complement system: serum C4 protein concentrations correlate with C4 gene size and polygenic variations, hemolytic activities, and body mass index. J Immunol 2003; 171: 2734-45.
[52]
Rigby WF, Wu YL, Zan M, et al. Increased frequency of complement C4B deficiency in rheumatoid arthritis. Arthritis Rheum 2012; 64: 1338-44.
[53]
Wu YL, Hauptmann G, Viguier M, Yu CY. Molecular basis of complete complement C4 deficiency in two North-African families with systemic lupus erythematosus. Genes Immun 2009; 10: 433-45.
[54]
Kingery SE, Wu YL, Zhou B, Hoffman RP, Yu CY. Gene CNVs and protein levels of complement C4A and C4B as novel biomarkers for partial disease remissions in new-onset type 1 diabetes patients. Pediatr Diabetes 2012; 13: 408-18.
[55]
Yang Y, Chung EK, Wu YL, et al. Gene copy-number variation and associated polymorphisms of complement component C4 in human systemic lupus erythematosus (SLE): low copy number is a risk factor for and high copy number is a protective factor against SLE susceptibility in European Americans. Am J Hum Genet 2007; 80: 1037-54.
[56]
Lintner KE, Wu YL, Yang Y, et al. Early Components of the Complement Classical Activation Pathway in Human Systemic Autoimmune Diseases. Front Immunol 2016; 7: 36.
[57]
Arason GJ, Kramer J, Blasko B, et al. Smoking and a complement gene polymorphism interact in promoting cardiovascular disease morbidity and mortality. Clin Exp Immunol 2007; 149: 132-8.
[58]
Blasko B, Kolka R, Thorbjornsdottir P, Sigurdarson ST, et al. Low complement C4B gene copy number predicts short-term mortality after acute myocardial infarction. Int Immunol 2008; 20: 31-7.
[59]
Kramer J, Harcos P, Prohaszka Z, et al. Frequencies of certain complement protein alleles and serum levels of anti-heat-shock protein antibodies in cerebrovascular diseases. Stroke 2000; 31: 2648-52.
[60]
Kramer J, Rajczy K, Hegyi L, et al. C4B*Q0 allotype as risk factor for myocardial infarction. BMJ 1994; 309: 313-4.
[61]
Mizuno H, Sato H, Sakata Y, et al. Impact of atherosclerosis-related gene polymorphisms on mortality and recurrent events after myocardial infarction. Atherosclerosis 2006; 185: 400-5.
[62]
Szilagyi A, Fust G. Diseases associated with the low copy number of the C4B gene encoding C4, the fourth component of complement. Cytogenet Genome Res 2008; 123: 118-30.
[63]
Arason GJ, Bodvarsson S, Sigurdarson ST, et al. An age-associated decrease in the frequency of C4B*Q0 indicates that null alleles of complement may affect health or survival. Ann N Y Acad Sci 2003; 1010: 496-9.
[64]
Kramer J, Rajczy K, Fust G. Low incidence of null alleles of the fourth component of complement (C4) in elderly people. Immunol Lett 1989; 20: 83-5.
[65]
Flachsbart F, Caliebe A, Heinsen FA, et al. Investigation of complement component C4 copy number variation in human longevity. PLoS One 2014; 9: e86188.
[66]
Bomback AS. Anti-complement therapy for glomerular diseases. Adv Chronic Kidney Dis 2014; 21: 152-8.
[67]
Risitano AM. Anti-complement treatment in paroxysmal nocturnal hemoglobinuria: where we stand and where we are going. Transl Med UniSa 2014; 8: 43-52.
[68]
Thurman JM. New anti-complement drugs: not so far away. Blood 2014; 123: 1975-6.
[69]
Mastellos DC, Yancopoulou D, Kokkinos P, et al. Compstatin: a C3-targeted complement inhibitor reaching its prime for bedside intervention. Eur J Clin Invest 2015; 45: 423-40.


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Article Details

VOLUME: 15
ISSUE: 1
Year: 2019
Page: [44 - 48]
Pages: 5
DOI: 10.2174/1573399814666180417122030
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