Intestinal ABCA1 is a potential target for raising HDL cholesterol

GW3965, a synthetic liver X receptor (LXR) agonist, may have potential as a new tool for raising high-density lipoprotein (HDL) cholesterol levels. Data from a recent experimental study show that treatment with GW3965 substantially raises plasma HDL cholesterol levels, while avoiding systemic side effects.1

ATP-binding cassette A1 (ABCA1) is a cell membrane transporter that facilitates the delivery of cholesterol from cells to lipid-poor apolipoprotein AI (the main lipoprotein in HDL) in the extracellular space. ABCA1 is therefore a potentially attractive therapeutic target for raising HDL cholesterol levels. Recent data show that hepatic and intestinal ABCA1 are the main sites of HDL particle formation in vivo.2,3

LXR agonists are potent inducers of ABCA1 and are being investigated as possible new agents for raising HDL cholesterol levels. However, to date the potential therapeutic usefulness of these agents is compromised by systemic LXR activation, which leads to hypertriglyceridaemia and hepatic steatosis.

GW3965 is a synthetic LXR agonist that has been shown to effectively raise HDL cholesterol levels and inhibit atherosclerosis in animal models, without causing induction of genes responsible for lipogenesis in the liver. Researchers used two different genetically modified mouse models, mice lacking hepatic ABCA1 and mice lacking intestinal ABCA1, to investigate the specific treatment effects of GW3965. In mice lacking hepatic ABCA1 and control mice, treatment with GW3965 increased intestinal expression of ABCA1 by about 6-fold, without any change in hepatic expression. This led to a significant increase in HDL cholesterol levels, without any change in plasma triglycerides. However, this effect was completely absent in mice lacking intestinal ABCA1.

The authors concluded that intestinal ABCA1 may represent a promising therapeutic target for raising HDL cholesterol levels. LXR agonists that are specific for intestinal ABCA1 appear to avoid side effects normally associated with systemic LXR activation such as hepatic steatosis and hyperglyceridemia.

References

1. Brunham LR, Kruit JK, Pape TD et al. Tissue-specific induction of intestinal ABCA1 expression with a liver X receptor agonist raises plasma HDL cholesterol levels. Circ Res 2006;99:672-4.

2. Timmins JM, Lee JY, Boudyguina E et al. Targeted activation of hepatic Abca1 causes profound hypoalphalipoproteinemia and kidney hypercatabolism of apoA-I. J Clin Invest 2005;115:1333-42.

3. Brunham LR, Kruit JK, Iqbal J et al. Intestinal ABCA1 directly contributes to HDL biogenesis in vivo. J Clin Invest 2006;116:1052-62.

Commentary

This is an interesting paper that highlights a role for the intestine in HDL synthesis. It is well known that activity of the ABCA1 transporter in the liver contributes to HDL assembly in plasma and that an increase in its activity raises the level of HDL cholesterol. This paper shows that ABCA1 activity in the intestine also has this effect, suggesting that intestinal ABCA1 may be a worthwhile therapeutic target for increasing the concentration of HDL cholesterol.