PT  - JOURNAL ARTICLE
AU  - Hambruch, Eva
AU  - Miyazaki-Anzai, Shinobu
AU  - Hahn, Ulrike
AU  - Matysik, Silke
AU  - Boettcher, Alfred
AU  - Perović-Ottstadt, Sanja
AU  - Schlüter, Thomas
AU  - Kinzel, Olaf
AU  - Krol, Helen Desiree
AU  - Deuschle, Ulrich
AU  - Burnet, Michael
AU  - Levi, Moshe
AU  - Schmitz, Gerd
AU  - Miyazaki, Makoto
AU  - Kremoser, Claus
TI  - Synthetic Farnesoid X Receptor Agonists Induce High-Density Lipoprotein-Mediated Transhepatic Cholesterol Efflux in Mice and Monkeys and Prevent Atherosclerosis in Cholesteryl Ester Transfer Protein Transgenic Low-Density Lipoprotein Receptor (−/−) Mice
AID  - 10.1124/jpet.112.196519
DP  - 2012 Dec 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 556--567
VI  - 343
IP  - 3
4099  - http://jpet.aspetjournals.org/content/343/3/556.short
4100  - http://jpet.aspetjournals.org/content/343/3/556.full
SO  - J Pharmacol Exp Ther2012 Dec 01; 343
AB  - Farnesoid X receptor (FXR), a bile acid-activated nuclear hormone receptor, plays an important role in the regulation of cholesterol and more specifically high-density lipoprotein (HDL) homeostasis. Activation of FXR is reported to lead to both pro- and anti-atherosclerotic effects. In the present study we analyzed the impact of different FXR agonists on cholesterol homeostasis, plasma lipoprotein profiles, and transhepatic cholesterol efflux in C57BL/6J mice and cynomolgus monkeys and atherosclerosis development in cholesteryl ester transfer protein transgenic (CETPtg) low-density lipoprotein receptor (LDLR) (−/−) mice. In C57BL/6J mice on a high-fat diet the synthetic FXR agonists isopropyl 3-(3,4-difluorobenzoyl)-1,1-dimethyl-1,2,3,6-tetrahydroazepino[4,5-b]indole-5-carboxylate (FXR-450) and 4-[2-[2-chloro-4-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-4-isoxazolyl]methoxy]phenyl]cyclopropyl]benzoic acid (PX20606) demonstrated potent plasma cholesterol-lowering activity that affected all lipoprotein species, whereas 3-[2-[2-chloro-4-[[3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methoxy]phenyl]ethenyl]benzoic acid (GW4064) and 6-ethyl chenodeoxycholic acid (6-ECDCA) showed only limited effects. In FXR wild-type mice, but not FXR(−/−) mice, the more efficacious FXR agonists increased fecal cholesterol excretion and reduced intestinal cholesterol (re)uptake. In CETPtg-LDLR(−/−) mice PX20606 potently lowered total cholesterol and, despite the observed HDL cholesterol (HDLc) reduction, caused a highly significant decrease in atherosclerotic plaque size. In normolipidemic cynomolgus monkeys PX20606 and 6-ECDCA both reduced total cholesterol, and PX20606 specifically lowered HDL2c but not HDL3c or apolipoprotein A1. That pharmacological FXR activation specifically affects this cholesterol-rich HDL2 subclass is a new and highly interesting finding and sheds new light on FXR-dependent HDLc lowering, which has been perceived as a major limitation for the clinical development of FXR agonists.