Synthetic FXR agonist Px20606 lowers cholesterol in HDL2 but not in HDL3 subfractions and demonstrates anti-atherosclerotic effects

The Farnesoid X Receptor (FXR, NR1H4) is a member of the nuclear receptor superfamily that functions as an endogenous sensor for bile acids and regulates – amongst other effects on metabolism -cholesterol and fatty acid metabolism.

We studied the impact of different FXR agonists on cholesterol homeostasis, plasma lipoprotein profiles and transhepatic cholesterol efflux (Hambruch et al., J Pharmacol Exp Ther. 2012 Aug 23. epub).

In C57BL/6J mice on high-fat diet, the synthetic FXR agonists FXR-450 and PX20606 demonstrated potent plasma cholesterol lowering activity that affected all lipoprotein species, whereas GW4064 and 6-ECDCA showed only limited effects. In FXR wildtype but not FXR-/- mice the more efficacious FXR agonists increased fecal cholesterol excretion and reduced intestinal cholesterol (re)uptake.

Further we examined the effect of FXR activation on the development of atherosclerosis. In CETPtg LDLR-/- mice FXR agonist PX20606 potently lowered plasma total cholesterol as well as HDL-cholesterol. Despite the apparent HDL lowering, Px20606 caused a highly significant decrease in atherosclerotic plaque size.

FXR activation by PX20606 and 6-ECDCA led to similar cholesterol reductions in normolipidemic Cynomolgus monkeys. Lipoprotein separation by ultracentrifugation showed that PX20606 specifically lowered HDL2c but not HDL3c nor ApoAI protein.

That the same FXR agonist Px20606 affects the cholesterol-rich HDL2 subclass and shows anti-atherosclerotic effects is a new and highly interesting finding and sheds a new light on the FXR effects on HDLc lowering which are so far perceived as a major limitation for clinical development of FXR agonists.