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

• Published in: The Journal of pharmacology and experimental therapeutics 2012-12, Vol.343 (3), p.556-567
• Main Authors: Hambruch, Eva, Miyazaki-Anzai, Shinobu, Hahn, Ulrike, Matysik, Silke, Boettcher, Alfred, Perović-Ottstadt, Sanja, Schlüter, Thomas, Kinzel, Olaf, Krol, Helen Desiree, Deuschle, Ulrich, Burnet, Michael, Levi, Moshe, Schmitz, Gerd, Miyazaki, Makoto, Kremoser, Claus
• Format: Article
• Language: English
• Subjects: Animals; Anticholesteremic Agents - chemistry; Anticholesteremic Agents - pharmacology; Anticholesteremic Agents - therapeutic use; Aorta - drug effects; Aorta - metabolism; Aorta - pathology; Atherosclerosis - blood; Atherosclerosis - metabolism; Atherosclerosis - prevention & control; Benzoates - chemistry; Benzoates - pharmacology; Benzoates - therapeutic use; Biological Transport; Cholesterol - administration & dosage; Cholesterol - blood; Cholesterol - metabolism; Cholesterol Ester Transfer Proteins - genetics; Cholesterol Ester Transfer Proteins - metabolism; Diet, High-Fat; Disease Models, Animal; Feces - chemistry; Female; Humans; Isoxazoles - chemistry; Isoxazoles - pharmacology; Isoxazoles - therapeutic use; Lipoproteins, HDL - blood; Liver - drug effects; Liver - metabolism; Macaca fascicularis; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Molecular Structure; Rats; Rats, Sprague-Dawley; Receptors, Cytoplasmic and Nuclear - agonists; Receptors, LDL - genetics; Receptors, LDL - metabolism; Species Specificity; Structure-Activity Relationship
• ISSN: 0022-3565; 1521-0103
• DOI: 10.1124/jpet.112.196519

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 HDL(2c) but not HDL(3c) or apolipoprotein A1. That pharmacological FXR activation specifically affects this cholesterol-rich HDL(2) 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.