Table of Contents
by the induction of RCT, which is a multi-step process that results in the elimination of cholesterol from the body. In RCT, cholesterol is actively transported out of peripheral cells onto
HDL, and the excess cholesterol is transported to the liver and eliminated from the body. We believe activation of cholesterol removal from plaque by RCT will provide a novel avenue to remove
cholesterol, and is expected to reduce plaque burden and to provide additional protection for ACS patients.
Inflammation plays an important role in ACS. Macrophages, other types of white blood cells and other inflammatory cells have been shown
to infiltrate the atherosclerotic plaque. These inflammatory cells synthesize and secrete additional pro-inflammatory proteins that further increase the inflammatory process, as well as alter the
endothelial surface, the thin layer of cells that lines the interior surface of blood vessels, of the plaque and make it prone to the formation of blood clots which can block the artery. In addition,
the activated macrophages secrete proteases, a type of enzyme, which breaks down the extracellular proteins in the plaques and weakens the cap of the plaque, thereby predisposing the plaque to
rupture. A ruptured plaque often results in the formation of blood clots which can block the artery, leading to a MI. Thus, the active inflammatory process in ACS atherosclerotic plaques exacerbates
the disease process.
Liver X receptors, LXRs, which include, LXRa and LXRb, work
to transport cholesterol out of cells as shown in Figure 13 below and inhibit the production of inflammatory proteins. VTP-38443 targets LXRb within
macrophages in the atherosclerotic plaque in the vessel walls to remove cholesterol and decrease the production of inflammatory proteins. Clinical trials have established that
LXRb is a major regulator of ABCA1, a cellular membrane transporter that moves cholesterol out of cells and on to HDL-C. A transporter related to ABCA1, called
ABCG1, was also identified as a cholesterol exporter that is also regulated by LXRs. LXRa is mainly found in liver, kidney and intestine.
LXRb is expressed in most organs and tissues. Several studies have demonstrated that LXR agonists will promote RCT in
vivo in mice and prevent the development of atherosclerosis. However, undesired activation of LXRa can induce fatty acid production in
liver, resulting in a fatty liver and elevated plasma TGs. Therefore, it is desirable to develop LXR modulators that are agonists for LXRb while avoiding activity
of LXRa to reduce effects on liver and plasma TGs.
Figure 13: Activation of LXRs increases the synthesis of cholesterol transporters ABCA1 and ABCG1 which leads to cholesterol efflux on Apolipoprotein A1, or
ApoA-1, containing lipoproteins. ApoA-1 is the major protein associated with HDL-C.