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.
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.
Phenex Pharmaceuticals AG, Heidelberg, Germany.
Eva
E
Hambruch
Shinobu
S
Miyazaki-Anzai
Ulrike
U
Hahn
Silke
S
Matysik
Alfred
A
Boettcher
Sanja
S
Perović-Ottstadt
Thomas
T
Schlüter
Olaf
O
Kinzel
Helen Desiree
HD
Krol
Ulrich
U
Deuschle
Michael
M
Burnet
Moshe
M
Levi
Gerd
G
Schmitz
Makoto
M
Miyazaki
Claus
C
Kremoser
D000818:Animals; D000924:Anticholesteremic Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D001011:Aorta / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D050197:Atherosclerosis / Q000097:blood / Q000378:metabolism / Q000517:prevention & control*; D001565:Benzoates / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D001692:Biological Transport; D002784:Cholesterol / Q000008:administration & dosage / Q000097:blood* / Q000378:metabolism; D053480:Cholesterol Ester Transfer Proteins / Q000235:genetics / Q000378:metabolism*; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D005243:Feces / Q000737:chemistry; D005260:Female; D006801:Humans; D007555:Isoxazoles / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D008075:Lipoproteins, HDL / Q000097:blood*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D015394:Molecular Structure; D051381:Rats; D017207:Rats, Sprague-Dawley; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists*; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism*; D013045:Species Specificity; D013329:Structure-Activity Relationship; D000099150:Receptor, Farnesoid X-Activated
D000924:Anticholesteremic Agents; D001565:Benzoates; D002784:Cholesterol; D053480:Cholesterol Ester Transfer Proteins; D007555:Isoxazoles; D008075:Lipoproteins, HDL; D018160:Receptors, Cytoplasmic and Nuclear; D011973:Receptors, LDL; D000099150:Receptor, Farnesoid X-Activated; C000598201:4-(((6-((5-cyclopropyl-3-(2,6-dichlorophenyl)-4-isoxazolyl)methoxy)-2-(trifluoromethyl)-3-pyridinyl)methylamino)methyl)benzoic acid; C000598200:4-(2-(2-chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)-4-isoxazolyl)methoxy)phenyl)cyclopropyl)benzoic acid