Elsevier

Molecular Immunology

Volume 61, Issue 2, October 2014, Pages 135-148
Molecular Immunology

The complement system in human cardiometabolic disease

https://doi.org/10.1016/j.molimm.2014.06.031Get rights and content

Highlights

  • Complement plays a role in immune, inflammatory and metabolic processes.

  • Complement may be involved in obesity-induced adipose tissue inflammation.

  • Complement is associated with metabolic syndrome, diabetes and fatty liver disease.

  • Complement is associated with several aspects of cardiovascular disease.

  • The various activation pathways may have specific roles in cardiometabolic disease.

Abstract

The complement system has been implicated in obesity, fatty liver, diabetes and cardiovascular disease (CVD). Complement factors are produced in adipose tissue and appear to be involved in adipose tissue metabolism and local inflammation. Thereby complement links adipose tissue inflammation to systemic metabolic derangements, such as low-grade inflammation, insulin resistance and dyslipidaemia. Furthermore, complement has been implicated in pathophysiological mechanisms of diet- and alcohol induced liver damage, hyperglycaemia, endothelial dysfunction, atherosclerosis and fibrinolysis.

In this review, we summarize current evidence on the role of the complement system in several processes of human cardiometabolic disease. C3 is the central component in complement activation, and has most widely been studied in humans. C3 concentrations are associated with insulin resistance, liver dysfunction, risk of the metabolic syndrome, type 2 diabetes and CVD. C3 can be activated by the classical, the lectin and the alternative pathway of complement activation; and downstream activation of C3 activates the terminal pathway. Complement may also be activated via extrinsic proteases of the coagulation, fibrinolysis and the kinin systems. Studies on the different complement activation pathways in human cardiometabolic disease are limited, but available evidence suggests that they may have distinct roles in processes underlying cardiometabolic disease. The lectin pathway appeared beneficial in some studies on type 2 diabetes and CVD, while factors of the classical and the alternative pathway were related to unfavourable cardiometabolic traits. The terminal complement pathway was also implicated in insulin resistance and liver disease, and appears to have a prominent role in acute and advanced CVD.

The available human data suggest a complex and potentially causal role for the complement system in human cardiometabolic disease. Further, preferably longitudinal studies are needed to disentangle which aspects of the complement system and complement activation affect the different processes in human cardiometabolic disease.

Section snippets

Cardiometabolic disease

Cardiometabolic disease describes a spectrum of interconnected pathobiological alterations in metabolic organs and the cardiovascular system that alone and in concert increase cardiovascular disease burden (Castro et al., 2003, Gill et al., 2005). Our modern lifestyle, with excess energy intake and sedentary behaviour, forms the basis for the current epidemic of overweight and obesity. Central obesity, i.e. the accumulation of fat in and around the abdominal area, is associated with

The complement system

The complement system is a complex protein network of the innate immune system. It consists of soluble and membrane-bound proteins functioning in cascades of stepwise protease activation (Ricklin et al., 2010). Complement can be activated by three major pathways, the classical pathway, the lectin pathway and the alternative pathway (Noris and Remuzzi, 2013). Activation of any of the three pathways can lead to the cleavage of C3, and subsequent activation of C5, C6, C7, C8 and C9 of the terminal

The complement system in adipose tissue

Adipose tissue is considered a metabolically active immune organ (Makki et al., 2013). It is also a source and a target of many complement factors. Human adipose tissue produces and secretes many factors of the classical, lectin, alternative and terminal pathways (Table 1). In vivo, both adipose and non-adipose cells (such as endothelial cells or macrophages) are likely to contribute to adipose tissue complement production, but studies using isolated adipocytes have shown that at least C1q,

The complement system in low-grade inflammation and insulin resistance

The above-described relations between complement and adiposity strongly suggest a role for the complement system also in systemic inflammation and systemic insulin resistance. In large studies (n > 1000), C3, C4, MBL and FD correlated with plasma C-reactive protein (CRP) or with other inflammatory markers (Engstrom et al., 2005a, Keller et al., 2006, Luc et al., 2010, Onat et al., 2010). Furthermore, plasma C1q, FB, FH, properdin, C1-INH and C4BP correlated with CRP in smaller studies (n < 300) (

The complement system in the metabolic syndrome and type 2 diabetes

The association of complement with systemic insulin resistance and inflammation suggests that complement might also contribute to DM2 and MetS, which is a strong risk factor for DM2. Complement C3 is elevated in MetS in persons of different ethnicities and is correlated with the number of overt MetS components (Ajjan et al., 2007, Ohsawa et al., 2010, Phillips et al., 2009, Phillips et al., 2012, Ylitalo et al., 2001). The association between C3 and prevalent MetS was shown to be independent of

The complement system in fatty liver disease

The liver plays a pivotal role in the metabolic impairments that result from obesity-induced inflammation, insulin resistance and dyslipidaemia. Non-alcoholic fatty liver disease (NAFLD) is regarded to be the liver manifestation of the MetS and DM2, and up to 80% of obese individuals have been reported to have some form of NAFLD (Bellentani et al., 2010). In fact, hepatic fat accumulation rather than (central) adiposity itself has been proposed as the cause of systemic insulin resistance (

Complement in cardiovascular disease

Cardiovascular disease (CVD) is a major clinical manifestation of cardiometabolic disorders and is characterized by critically narrowing (stenosis) or occlusion (atherothrombosis) of blood vessels. Coronary heart disease comprises partial or complete obstruction of coronary vessels, while the term CVD additionally includes partial or complete obstruction of peripheral or cerebral vessels. Key processes in CVD are endothelial dysfunction, atherosclerosis, and impaired regulation of coagulation

Lifestyle factors and drugs that influence complement

Given the multi-facetted implications of complement in cardiometabolic disease, it appears valuable to consider the effect of modifiable lifestyle factors and commonly prescribed drugs on complement. Circulating C3 was in observational studies associated with dietary intake of provitamin A, selenium status and dietary anti-oxidant intake (Puchau et al., 2009, Puchau et al., 2010, van Greevenbroek et al., 2014). An experimental study that compared the effects of two hypocaloric diets on C3 found

Conclusion

The above-presented data suggest that the complement system may provide a link between adipose tissue inflammation and systemic metabolic derangements that promote human cardiometabolic disease (Fig. 1). Complement appears to play a role in general but also in specific processes of cardiometabolic disease, such as lipid metabolism, hyperglycaemia and fibrinolysis. A large array of studies has investigated C3, and shown independent associations with insulin resistance, liver dysfunction and in

Acknowledgement

The Ph.D. fellowship of E Hertle was supported by the Dutch Heart Foundation (NHS2010B194).

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