Postprandial inflammation and endothelial dysfuction

Physiology of postprandial lipaemia

The fact that both fasting plasma TAG and HDL-C (high-density lipoprotein cholesterol) predict CHD (coronary heart disease) is not unexpected since both are closely inversely correlated. This is due to the fact that HDL-C is partly formed during the physiological metabolism of TRLs (TAG-rich lipoproteins) [7]. In addition, when hypertriglyceridaemia is present, highly atherogenic small-dense LDL (low-density lipoprotein) will be generated, increasing the atherogenic potential of plasma. These particles are highly atherogenic after oxidative or glycaemic modification, due to the processing by up-regulated scavenger receptors on activated monocytes, transforming them into macrophages and eventually leading to foam cell formation [8]. A high prevalence of small-dense LDL is very common in patients with the metabolic syndrome, diabetes mellitus and insulin resistance in general [9,10].

TRLs are mainly produced postprandially and people in the Western world are non-fasting for most of the day, which leads to a continuous challenge of the endothelium by atherogenic lipoprotein remnants [11,12]. Endogenous TRLs [VLDL (very low-density lipoprotein)] and exogenous TRLs (chylomicrons) share the same metabolic pathway, e.g. endothelium-bound LPL (lipoprotein lipase) that hydrolyses TAGs into glycerol and three fatty acids. Increased levels of NEFAs [non-esterified (‘free’) fatty acids] as a result of obesity and, more importantly, due to a hypercaloric diet, are regarded as one of the key aetiological components of the metabolic syndrome [13]. In the postprandial phase due to limited LPL availability, competition at the level of LPL will occur, resulting in accumulation of TRLs. This competition is most likely when fasting hypertriglyceridaemia is present, as occurs in the metabolic syndrome, Type 2 diabetes and FCHL (familial combined hyperlipidaemia) [14]. However, it has also been suggested that of all patients with premature CHD, 40% have normal fasting plasma lipids [15], whereas most of these patients have impaired clearance of postprandial lipoproteins [4,16,17]. Atherosclerosis has therefore been considered to be a postprandial phenomenon [18,19].

Chylomicrons and inflammation

Atherosclerosis is considered a low-grade chronic inflammatory disease [20]. Many inflammatory markers have been associated with CHD such as CRP (C-reactive protein), leucocyte count and complement C3 [3,16,21–26]. However, several studies with animal models showed reduced plaque formation [27,28] and prevention of endothelial dysfunction [29] when adherence of leucocytes to the endothelium was prevented. These findings support the theory that the process of atherogenesis in part starts with leucocyte–endothelium interaction and adherence. Obligatory for this adherence is a cytokine-controlled sequential up-regulation of selectins and adhesion molecules on activated leucocytes and endothelial cells [30].

Van Oostrom et al. have shown that postprandially, when TAG and glucose rise, neutrophil counts increase, with concomitant production of pro-inflammatory cytokines and oxidative stress, and that these changes may contribute to endothelial dysfunction [31,32]. Furthermore, TAG and glucose are able to induce leucocyte activation, as has been shown in vitro [33] and ex vivo in hypertriglyceridaemic patients [34]. In healthy volunteers and in patients with premature atherosclerosis, postprandial lipaemia was associated with the up-regulation of leucocyte activation markers [35,36]. Fasting leucocytes of patients with CVD have an increased lipid content when compared with controls and it was suggested that this was due to the uptake of chylomicrons in the bloodstream [37]. Leucocytes are also able to take up retinyl esters, as markers of intestinally derived TRLs [38]. Recently, we have shown that apolipoprotein B binds to neutrophils and monocytes and that postprandial leucocytes transport dietary fatty acids [39]. This opens the possibility that direct activation of leucocytes may occur in the blood by interaction with chylomicrons and their remnants (Figure 1). Another aspect of postprandial lipaemia involves endothelial dysfunction. Many endothelium-derived factors play a role in vasomotion, permeability, proliferation and vascular smooth cell migration; NO (nitric oxide) is clearly one of the key players [40]. In the metabolic syndrome, but also in healthy subjects, elevations in fasting and postprandial TAGs have been related to increased carotid IMT (intima-media thickness) [41] and reductions in NO-dependent post-ischaemic FMD (flow-mediated dilation) of the brachial artery [42,43]. The reduction of FMD correlates with TAG and NEFA concentrations and is reversible in postprandial studies when TAG concentrations decrease at the end of the experiment [43]. Furthermore, postprandial lipoproteins have been shown to induce expression of leucocyte adhesion molecules on the endothelium, facilitating recruitment of inflammatory cells [44]. The effects of TRLs on the endothelium appear to be related to oxidative stress generation [31,45].

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Figure 1 Concept of the initiation of atherosclerosis in the bloodstream

Remnants, glucose and C3b are able to induce monocyte and neutrophil activation. This will lead to adherence of these cells to the endothelium as well as to the production of chemoattractants leading to the recruitment and activation of other leucocytes. Furthermore, these activated leucocytes can activate the endothelium by the expression of CAMs (cellular adhesion molecules) and selectins, facilitating adherence of all leucocytes, including lymphocytes. The activated leucocytes can also destabilize atherosclerotic lesions by the production of ROS (reactive oxygen species) and TNFα (tumour necrosis factor α). Monocytes and lymphocytes transmigrate across the endothelial wall. Activated neutrophils cannot transmigrate through the endothelial barrier, however they are able to degranulate, resulting in release of degradative enzymes such as collagenase and gelatinase. Monocytes residing in the arterial wall become activated as a result of proinflammatory cytokines and differentiate into macrophages (MΦ). LDL and remnant particles can enter the vessel wall as well. Oxidative modification of LDL results in a highly atherogenic particle that can easily be taken up by macrophages via the scavenger receptor (CD36). Activated monocytes and macrophages in the vessel wall can activate endothelial cells, resulting in production of CAMs and cytokines such as IL-6 and 8 (interleukin-6 and 8) and MCP-1 (monocyte chemoattractant protein-1). These effects combined will lead to recruitment and activation of leucocytes, as expressed by increased selectins and integrins on the outer membrane. Other activated leucocytes are attracted to the activated endothelium and will eventually firmly adhere to the vessel wall. Monocytes and lymphocytes can then transmigrate through the endothelial barrier.

Another inflammatory marker related to CHD is complement system. The C3/ASP (C3/acylation-stimulating protein) system has been recognized as a regulator of adipose tissue fatty acid metabolism [46]. ASP is identical to the desarginated form of the C3 split product C3a (C3a-desArg), which is immunologically inactive. The C3/ASP pathway stimulates re-esterification of NEFAs into TAG in adipocytes, reduces adipocyte NEFA production by inhibiting hormone-sensitive lipase and stimulates glucose uptake by adipocytes, fibroblasts and muscle cells [46]. C3 is a strong predictor of myocardial infarction [26] and it has been positively associated with obesity, CAD (coronary artery disease), insulin resistance, the metabolic syndrome [3], fasting and postprandial TAG and hypertension [16,26]. Deposition of complement co-localized with CRP has been observed in atherosclerotic plaques [47] and complement activation also plays a role in the induction of tissue damage after myocardial infarction [48]. Moreover, chylomicrons are the strongest in vitro and in vivo stimulators of adipocyte C3 production via activation of the alternative complement cascade [24,49]. A postprandial C3 increment after a fat meal has been shown in healthy subjects and in patients with CAD and with FCHL [16,24,25]. The postprandial increment has been related to TAG and NEFA metabolism [5].

Since C3 and leucocytes increase postprandially, especially after fat intake, and leucocytes become activated during the postprandial phase, a potential mechanism may be the generation of oxidative stress [31,39]. Many factors have been suggested to participate in this process. PON-1 (paraoxonase 1), a potent antioxidant closely associated with HDL-C seems to be a key player [50]. During postprandial lipaemia, HDL-C tends to decrease, impairing the reverse cholesterol transport, again providing an extra atherogenic mechanism for postprandial lipaemia.