The complement system 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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This article belongs to SI: XXV ICW Rio 2014.