CLA-1/SR-BI protein may promote cholesterol removal from peripheral cells Figure 84 The CLA-1 receptor is the human homolog of the SR-I receptor in mice. This receptor: promotes the efflux of cholesterol from peripheral cells; and acts as a ‘docking receptor’ promoting the capture of cholesterol by the liver and tissues involved in steroidogenesis (e.g. adrenal glands, ovary).

CLA-1 expression is regulated by PPARa activators in differentiated human macrophages Figure 85 CLA-1 receptor production in human macrophages increases in a dose-dependent manner with increasing doses of fenofibrate.

PPARa activators induce cholesterol efflux and reverse cholesterol transport Figure 86 Summary of the effects of PPARa activators: increased production of apo A-I and A-II giving rise to increased formation of HDL; results in VLDL which is low in apo C-III thereby reducing the formation of small, dense LDL; increases ABCA-1 expression thereby increasing cholesterol efflux; increases SR-BI (CLA-1) expression thereby increasing reverse cholesterol transport; increases LPL activity which increases lipolysis; increases apo A-V production thereby decreasing TG levels.

PPARs in the vascular wall Figure 87 Using specific antibodies against PPARa and PPARg, it was possible to demonstrate that PPARs are not only located in the liver and muscles but also in various cells of the arterial wall. The specific location of PPARs within the wall is as follows: PPARa - smooth muscle cells, endothelial cells and macrophages; PPARg - endothelial cells and macrophages.

Mechanisms of transrepression by PPARa Figure 88 When PPARa is activated in the arterial wall, it causes transrepression of two other transcription factors involved in vascular inflammation – NFkB and AP-1. These transcription factors are normally activated by cytokines and are transferred to nuclear receptors, where they induce the synthesis of proteins involved in the inflammatory response.

The transcription factor NFkB: a key role in the inflammatory response Figure 89 Following activation by cytokines, the active part of NFkB is translocated to the nucleus, where it induces the synthesis of pro-inflammatory proteins (e.g. IL-6, COX-2, TNFa, etc).

Model of NFkB signal pathway inhibition by PPARa activators Figure 90 Activated PPARa inhibits the NFkB signal pathway by two mechanisms: synthesis of IkB, which is an inhibitor of NFkB; direct inhibition of the active form of NFkB translocated in the nucleus.

PPARa activated by fibrates inhibits IL-1b induced expression of COX-2 in SMC Figure 91 Evidence of the anti-inflammatory effect of PPARa agonists is provided by studies of human smooth muscle cells. After exposure to fenofibrate, there is inhibition of IL-1b expression of COX-2. Fenofibrate activates PPARa in a dose-dependent manner; similarly COX-2 expression decreases in a dose-dependent manner.