Complement C3: an emerging risk factor in cardiometabolic disease

Abstract

C3 is the central component of the complement system and activation of C3 via any of the three major activation pathways—the classical, the lectin and the alternative pathways—results in initiation of the terminal complement pathway and release of the anaphylatoxin C3a. Both terminal pathway activation and signalling of C3a and its inactivation product C3a-desarg via the C3a receptor and C5a-like receptor 2, respectively, can induce inflammatory, immunomodulatory and metabolic responses. C3 has been implicated in metabolic disorders, notably adiposity, dyslipidaemia, insulin resistance, liver dysfunction and diabetes, and C3 is increasingly recognised as a cardiometabolic risk factor. C3 may play a role in the macrovascular, as well as microvascular, complications of diabetes. Moreover, C3 may interact with the coagulation system and as such also contribute to a procoagulant, hypofibrinolytic and, ultimately, prothrombotic state. Recent data suggest a diabetes-dependent incorporation of C3 into fibrin clots, with concomitant effects on clot characteristics. Taken together, epidemiological and experimental evidence concordantly point to a role of complement C3 in metabolic, atherosclerotic/atherothrombotic and microangiopathic processes and further research should be directed towards the elucidation of complement function and activation in cardiometabolic disorders.

Complement Component 3 Is Associated with Metabolic Comorbidities in Older HIV-Positive Adults

“…[10][11][12][13][14][15] Higher C3 is also associated with nonalcoholic fatty liver disease, the primary liver manifestation of MetS, and may contribute to the impaired liver function and dyslipidemia observed in cardiometabolic disease. 16,17 The complement system has been hypothesized to play a role in the development of MetS and may be involved in deranged postprandial lipid metabolism in this setting. [18][19][20] C3 may play a particularly strong role in HIV-associated cardiometabolic disease.…”

Complement Factor 3 Is Associated With Insulin Resistance and With Incident Type 2 Diabetes Over a 7-Year Follow-up Period: The CODAM Study

“…Complement factor 3 (C3) is an emerging risk marker for cardiovascular and metabolic diseases (1,2), and systemic C3 concentrations are closely linked to several measures of body fat and components of the metabolic syndrome (3,4). Complement C3 is produced mainly by the liver (5), but other production sites, such as adipose tissue, may also contribute to systemic C3 levels (6).…”

Engineered Nanomaterial Impact in the Liver following Exposure via an Intravenous Route–The Role of Polymorphonuclear Leukocytes and Gene Expression in the Organ

“…Moreover, C3 might be capable of interaction with the coagulation system and contributing to pro-coagulation, and ultimately, a prothrombotic state [31]. The decrease in C3 expression might suggest that exposure to low doses of NMs in this study results in overall tolerance in the liver, rather than a fully developed immune response.…”