title: The complement system in human 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.
authors.affiliation: Department of Internal Medicine and CARIM School for Cardiovascular Diseases, Maastricht University Medical Centre, PO Box 616, Maastricht 6200, MD, The Netherlands.
authors.forename: E
authors.initials: E
authors.lastname: Hertle
authors.affiliation: Department of Internal Medicine and CARIM School for Cardiovascular Diseases, Maastricht University Medical Centre, PO Box 616, Maastricht 6200, MD, The Netherlands.
authors.forename: C D A
authors.initials: CD
authors.lastname: Stehouwer
authors.affiliation: Department of Internal Medicine and CARIM School for Cardiovascular Diseases, Maastricht University Medical Centre, PO Box 616, Maastricht 6200, MD, The Netherlands. Electronic address: m.vangreevenbroek@maastrichtuniversity.nl.
authors.forename: M M J
authors.initials: MM
authors.lastname: van Greevenbroek
mesh_terms: D000273:Adipose Tissue / Q000276:immunology / Q000378:metabolism; D000818:Animals; D002318:Cardiovascular Diseases / Q000150:complications* / Q000175:diagnosis / Q000209:etiology*; D003165:Complement System Proteins / Q000276:immunology* / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000378:metabolism; D007333:Insulin Resistance; D008659:Metabolic Diseases / Q000150:complications* / Q000175:diagnosis / Q000209:etiology*
chemical_list: D003165:Complement System Proteins
keywords: Cardiovascular disease; Complement system; Diabetes; Fatty liver disease; Insulin resistance; Obesity