The metabolic syndrome in relation to complement component 3 and postprandial lipemia in patients from an outpatient lipid clinic and healthy volunteers

Abstract

We investigated the relationship between complement component 3 (C3), fasting and postprandial lipemia and the metabolic syndrome (MetabS). Herefore fasting and postprandial samples after an acute oral fat load were obtained in 40 MetabS+ (50 ± 8 years) and 70 MetabS− (48 ± 7 years) subjects. Fasting C3 was higher in MetabS+ (1.21 ± 0.33 g/L versus 0.91 ± 0.14 g/L, P < 0.001). Postprandially, MetabS+ had a higher total and incremental triglyceride response (TG-AUC: +77%; P < 0.001 and TG-dAUC: +48%; P < 0.05, respectively) and a higher total free fatty acid (FFA-AUC: +13%, P < 0.05) and C3 response (C3-AUC: +26%, P < 0.001) when compared to MetabS−. In both groups, fasting C3 was strongly associated with fasting TG, TG-AUC, TG-dAUC and insulin sensitivity (HOMA) (R = 0.68, 0.67, 0.41 and 0.67, respectively, for the whole group; P < 0.001 for each). Fasting C3 showed a dose-dependent relation with the number of MetabS components and, following exclusion of these components, it was after TG-AUC, the second best determinant of the MetabS (adjusted R² = 0.47, P < 0.001).

In conclusion, C3 and postprandial lipema are closely associated with the metabolic syndrome and with several metabolic variables linked to insulin resistance. C3 may be a useful marker to identify subjects with the metabolic syndrome.

Introduction

The insulin resistance syndrome was initially described by Reaven in 1988 [1] and recently redefined as the metabolic syndrome (MetabS) by the National Cholesterol Education Program's Adult Treatment Panel III report [2], [3]. The MetabS is a very common cause of type 2 diabetes, both conditions show rapidly increasing incidences in Western societies and are strongly associated with coronary artery disease (CAD) [3], [4].

Very recently, elevated concentrations of complement component 3 (C3), a protein with a central role in the innate immune system, have been associated with the development of diabetes [5]. By analogy, an association between MetabS and C3 may be expected. Elevation of plasma C3 has also been linked to CAD, obesity and elevated fasting and postprandial TG [6], [7], but the mechanism behind these associations remains unclear. Upon complement activation, C3 is produced by the liver and at sites of inflammation such as in atherosclerotic lesions [8]. Recently the C3/acylation stimulating protein (C3/ASP) system has been recognized as a regulator of adipose tissue fatty acid (FA) metabolism [8]. ASP is identical to the desarginated form of the C3 split-product C3a (C3a-desArg), which is immunologically inactive. The C3/ASP pathway stimulates the uptake and reduces the release of FA by adipocytes and stimulates glucose uptake by adipocytes, fibroblasts and muscle cells [8]. Chylomicrons are the strongest in vitro and in vivo stimulators of adipocyte C3 production via activation of the alternative complement cascade [9], [10]. Supporting this concept, a postprandial C3 increment after a standardized fat meal has been shown in healthy subjects, in CAD patients and in familial combined hyperlipidemia (FCHL) [6], [9], [11], [12]. In these studies the postprandial C3 increment was related to TG and FFA metabolism [13].

The MetabS is characterized by fasting and postprandial hypertriglyceridemia, which has been linked to an increased hepatic flux of free fatty acids (FFA) originating from the (visceral) adipose tissue [14], [15]. Impaired FA metabolism, in particular postprandially, is thought to play a pivotal role in the pathogenesis of the MetabS [16], [17]. FFA elevation is thought to contribute directly to peripheral tissue insulin resistance [18] and endothelial dysfunction [19], [20]. By analogy with insulin, elevated C3 may point to C3/ASP resistance [6], [11]. In the present study, we examined this concept in relation to postprandial triglyceride and FFA metabolism in a group of subjects with or without the MetabS.