Complement C3 and C4 and Metabolic Syndrome

The complement system is part of the innate immune system and plays a role in regulating inflammation. Increased inflammation is engaged in the development of adult cardiometabolic diseases such as insulin resistance, dyslipidemia, atherosclerosis, and hypertension. Adipose tissue not only produces complement but is also a potential target for complement activity. Obese adults and adults with cardiometabolic disease who are not obese have been shown to have increased complement levels. If not regulated appropriately, activated complement components have the potential to harm the host. Here we review complement physiology, complement genetics and its association to metabolic syndrome. Melanie Copenhaver1, Chack-Yung Yu2 and Robert P Hoffman1* 1Department of Pediatrics, Nationwide Children’s Hospital, USA 2The Research Institute at Nationwide Children’s Hospital, USA Robert P Hoffman, et al., Annals of Diabetes Research Remedy Publications LLC. 2017 | Volume 1 | Issue 1 | Article 1003 2 cleavage of C4 to C4b, the large fragment of C4 that covalently binds to the surface of the pathogen, and C4a, that is analogous to C3a and C5a in primary structures but its functions are not well defined. C4b in combination with C2a forms the C3 convertase for both of these pathways [11]. The anaphylatoxins C3a and C5a act on specific receptors to elicit inflammatory responses, induce smooth muscle contraction, and increase vascular permeability. C5a and C3a act on the endothelial cells lining blood vessels and can activate mast cells that release histamine and TNF-α which further contribute to the inflammatory response. In addition, they cause an increase in vessel diameter and fluid accumulation in tissues. The fluid accumulation increases lymphatic drainage which brings pathogens to lymph nodes [15]. These powerful inflammatory effects of the complement system have the potential to harm the host by causing tissue injuries. Thus, there is a series of complement regulatory proteins that downregulate complement activity on host cells but still allow activation on foreign targets [14]. Disruption of this regulatory system with chronic complement activation may play a detrimental role in the development of cardiometabolic disease [16]. Complement, Obesity and Metabolic Risk As indicted above, serum complement component C3 is vital to the three complement activation pathways and increased inflammation (Figure 1). C3 is manufactured primarily by the liver but is also synthesized in adipocytes, macrophages and endothelial cells [17]. Chylomicrons with dietary fat stimulate adipocyte C3 production [18,19]. Serum C3 levels are strongly correlated with the Body Mass Index (BMI) of a subject and the rate of consumption due to chronic turnover or immune-mediated diseases, rather than through increased inflammation since the ratios of C3a/C3 are not altered in obesity [18,20]. C3a is rapidly cleaved by carboxypeptidases to remove the carboxyl terminal of arginine to generate C3a-desArg [19]. Adipocytes in addition to producing C3, also, have receptors for C3a (C3aR) and C5a (C5aR1 and C5aR2) [17]. Thus, adipose, in addition to producing complement, is a potential target of complement action, as well. The C5aRs is the only known receptor for C3a-desArg. C3a-desArg, also known as acylation stimulation factor, plays a role in transporting fatty acids to adipocytes and triacylglycerol synthesis. It accelerates adipocyte triglyceride metabolism and increases plasma triglyceride levels and this likely plays a role in increasing insulin resistance. Interestingly, C3 and C3aR knock-out mice are resistant to diet-induced obesity and more insulin sensitive than control mice [18]. Cross-sectional and longitudinal studies in adults have shown consistent relationships between complement (C3, C3a, C3a-desArg and C4) and a variety of cardiometabolic diseases and risk factors. Specifically C3, C3a and C3a-desArg levels positively correlate with measures of obesity and visceral obesity in most ethnic groups and both sexes [16,20,21-26]. Beyond this several studies have demonstrated increased C3 levels in adults with the metabolic syndrome independent of obesity [20,24,26-29], direct relationships with individual components of the metabolic syndrome including insulin resistance, impaired glucose tolerance, triglycerides and lipids [16,20,22,24-26,28,30]. Patients with coronary artery disease, myocardial infarction, stroke and type 2 diabetes have been found to have increased C3 levels [16,22,25]. Beyond this, Muscari et al. [31] found that increased C3 levels predicted future cardiac ischemic events in Italian men and women, and Oshawa et al. [24] found that changes in C3 predicted changes in insulin resistance measured using the Homeostatic Model Assessment (HOMA). Among Hungarian healthy subjects, Yang and colleagues found that serum C3 levels not only significantly correlated with Body Mass Index (BMI), but also triglycerides and total cholesterol levels. The positive relationship between C3 and BMI was stronger in males than in females [32]. C4 has been less well studied in metabolic syndrome. In 2003, Yang et al. [32] reported a positive correlation between serum C4 levels and BMI among Hungarian subjects and such relationship was Figure 1: Complement and the Metabolic Syndrome. Complement Component C3 is produced primarily by the liver but also by macrophages and adipocytes. In the classical pathway C4 is activated to C4a and C4b which in combination with C2a form a C3 convertase that activates C3 to C3a and C3b. C3b may associate with the C4b2a complex to form a C5 convertase, activating C5 to C5a and C5b. C3a, C5a and C3a desArg, a breakdown product of C3a increase inflammation, cause endothelial dysfunction and vascular smooth muscle contraction. C3a desArg also increases adipocyte free fatty acid uptake and triglyceride synthesis and release. The latter increases insulin resistance. Chylomicrons enhance the slow continuous breakdown of C3 through the Alternative Pathway or Tick-over. Black lines indicate production, green lines activating effects and red lines adverse effects in the metabolic syndrome. Robert P Hoffman, et al., Annals of Diabetes Research Remedy Publications LLC. 2017 | Volume 1 | Issue 1 | Article 1003 3 independent of C3 in regression analyses. Subsequently, Nilsson et al. [20] found significant positive relationships of serum C4 levels to BMI, waist-to-hip ratio, subcutaneous and visceral adipose, blood pressure, cholesterol, and triglycerides, and a negative relationship to High Density Lipoprotein Levels (HDL). Oshawa et al. [24] found significant relationships to BMI, triglycerides, and Low Density Lipoprotein Levels (LDL). The C4 gene is located on chromosome 6 and there is significant copy number variation among different human subjects. Studies in African-Americans, Asian Indians and Caucasians demonstrate a consistent direct correlation between C4 gene copy number and plasma C4 concentrations [33,34]. Low copy number is associated with decreased serum C4 levels [32,35,36] and increased risk of autoimmune disease including lupus, rheumatoid arthritis, dermatomyositis and possibly type 1 diabetes [37-41]. Associations between C4 gene copy number variation and cardiovascular risk have not been investigated in depth but C4 copy number has been associated with longevity. Different forms of C4 (acidic (C4A), basic (C4B), long (C4L) and short (C4S)) also exist and there is copy number variation for each. Low C4B copy number has been shown to be associated with increased cardiovascular risk in several studies [42-47] and decreased longevity in Hungarian subjects [48,49] and Icelandic smokers [42] while decreased C4L is associated with increased longevity in Germans [50].