PPARalpha in atherosclerosis and inflammation - PubMed (original) (raw)

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PPARalpha in atherosclerosis and inflammation

Fokko Zandbergen et al. Biochim Biophys Acta. 2007 Aug.

Abstract

Peroxisome proliferator-activated receptor (PPAR)alpha is a nuclear receptor activated by natural ligands such as fatty acids as well as by synthetic ligands such as fibrates currently used to treat dyslipidemia. PPARalpha regulates the expression of genes encoding proteins that are involved in lipid metabolism, fatty acid oxidation, and glucose homeostasis, thereby improving markers for atherosclerosis and insulin resistance. In addition, PPARalpha exerts anti-inflammatory effects both in the vascular wall and the liver. Here we provide an overview of the mechanisms through which PPARalpha affects the initiation and progression of atherosclerosis, with emphasis on the modulation of atherosclerosis-associated inflammatory responses. PPARalpha activation interferes with early steps in atherosclerosis by reducing leukocyte adhesion to activated endothelial cells of the arterial vessel wall and inhibiting subsequent transendothelial leukocyte migration. In later stages of atherosclerosis, evidence suggests activation of PPARalpha inhibits the formation of macrophage foam cells by regulating expression of genes involved in reverse cholesterol transport, formation of reactive oxygen species (ROS), and associated lipoprotein oxidative modification among others. Furthermore, PPARalpha may increase the stability of atherosclerotic plaques and limit plaque thrombogenicity. These various effects may be linked to the generation of PPARalpha ligands by endogenous mechanisms of lipoprotein metabolism. In spite of this dataset, other reports implicate PPARalpha in responses such as hypertension and diabetic cardiomyopathy. Although some clinical trials data with fibrates suggest that fibrates may decrease cardiovascular events, other studies have been less clear, in terms of benefit. Independent of the clinical effects of currently used drugs purported to achieve PPARalpha, extensive data establish the importance of PPARalpha in the transcriptional regulation of lipid metabolism, atherosclerosis, and inflammation.

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Figures

Figure 1

Figure 1. PPARα activation modulates the hepatic acute phase response

Hepatic expression of inflammatory cytokines – such as CRP, fibrinogen and SAA – is inhibited by PPARα, both under basal conditions and after stimulation with cytokines such as IL-1, IL-6 and TNFα from the circulation. CRP, C-reactive protein; IL-1, interleukin-1; IL-6, interleukin-6; SAA, serum amyloid A; TNFα, tumor necrosis factor α.

Figure 2

Figure 2. PPARα activation modulates reactivity of the vascular endothelium

Activation of PPARα in ECs decreases production and secretion of ET-1, which would be expected to decrease vasoconstriction and SMC proliferation. PPARα has been reported to increase levels of endothelial nitric oxide synthetase (eNOS), which is the enzyme responsible for NO generation. ENOS induction would be expected to increase NO production and thus increase vasodilatation. Increased NO decreases expression of VCAM-1, a key player in leukocyte adhesion to the endothelium. PPARα activation can directly decrease VCAM-1 expression, which is thought to involve inhibition of NFκB activity. eNOS, endothelial nitric oxide synthase; ET-1, endothelin-1; NO, nitric oxide; SMC, smooth muscle cell; VCAM-1, vascular cell adhesion molecule-1.

Figure 3

Figure 3. PPARα inhibits local inflammatory responses in the endothelium

PPARα activation in the vasculature inhibits adhesion of T-cells and dendritic cells to the endothelium through inhibition of VCAM-1 expression. PPARα activation also decreases expression of inflammatory cytokines such as IFN-γ, TNFα, IL-2 by Th1 cells. In addition, PPARα inhibits the induction of COX2 expression by SMCs activated in response to IL-1β. COX2, cyclooxygenase 2; IFN-γ, interferon- γ; IL-2, interleukin 2.

Figure 4

Figure 4. PPARα activation modulates atherosclerotic plaque formation at multiple levels

In addition to its effects on VCAM-1 expression, PPARα activation also purportedly limits macrophage foam cell formation by inhibiting oxidative modification of LDL and by promoting reverse cholesterol transport via increased SR-BI and ABCA1 expression. PPARα activation may also decrease plaque thrombogenicity by inhibiting expression of the procoagulant tissue factor (TF). PPARα activation may also repress expression of MMP9, an enzyme implicated in plaque rupture, and decrease SMC proliferation. MMP9, matrix metalloproteinase.

Figure 5

Figure 5. Specific pathways of lipoprotein metabolism activates PPARα

VLDL and HDL hydrolysis by LPL and EL respectively can generate PPARα activation. In response to the action of these enzymes on these lipoprotein substrates, PPARα target genes are regulated, including targets implicated in atherosclerosis, like VCAM-1. When these lipolytic pathways are integrated into PPAR responses, the possibility that other lipase regulators, like ApoCII and ApoAV, as well as LPL inhibitors like ApoCI, ApoCIII, Angptl3 and Angptl4 may also regulate PPAR activity becomes apparent. Angptl, angiopoietin-like protein; Apo, apoprotein; EL, endothelial lipase; HDL, high density lipoprotein; LPL, lipoprotein lipase; VLDL, very low density lipoprotein.

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