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 (-/-)...

Overview

Journal J Pharmacol Exp Ther

Specialty Pharmacology

Date 2012 Aug 25

PMID 22918042

Citations 42

Authors

Eva Hambruch

Shinobu Miyazaki-Anzai

Ulrike Hahn

Silke Matysik

Alfred Boettcher

Sanja Perovic-Ottstadt

Thomas Schluter

Olaf Kinzel

Helen Desiree Krol

Ulrich Deuschle

Michael Burnet

Moshe Levi

Gerd Schmitz

Makoto Miyazaki

Claus Kremoser

Affiliations

Soon will be listed here.

Abstract

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.

Citing Articles

The role of short-chain fatty acid in metabolic syndrome and its complications: focusing on immunity and inflammation.

Yu W, Sun S, Fu Q Front Immunol. 2025; 16:1519925.

PMID: 39991152 PMC: 11842938. DOI: 10.3389/fimmu.2025.1519925.

Bile acid activated receptors: Integrating immune and metabolic regulation in non-alcoholic fatty liver disease.

Biagioli M, Fiorucci S Liver Res. 2025; 5(3):119-141.

PMID: 39957845 PMC: 11791866. DOI: 10.1016/j.livres.2021.08.003.

Sex differences and testosterone interfere with the structure of the gut microbiota through the bile acid signaling pathway.

Duan X, Nie Y, Xie X, Zhang Q, Zhu C, Zhu H Front Microbiol. 2024; 15:1421608.

PMID: 39493843 PMC: 11527610. DOI: 10.3389/fmicb.2024.1421608.

Inhibition of hepatic bile salt uptake by Bulevirtide reduces atherosclerosis in Oatp1a1Ldlr mice.

Porteiro B, Roscam Abbing R, In Het Panhuis W, de Waart D, Duijst S, Bolt I J Lipid Res. 2024; 65(8):100594.

PMID: 39009243 PMC: 11382107. DOI: 10.1016/j.jlr.2024.100594.

Dose Prediction and Pharmacokinetic Simulation of XZP-5610, a Small Molecule for NASH Therapy, Using Allometric Scaling and Physiologically Based Pharmacokinetic Models.

Zhang L, Feng F, Wang X, Liang H, Yao X, Liu D Pharmaceuticals (Basel). 2024; 17(3).

PMID: 38543155 PMC: 10975475. DOI: 10.3390/ph17030369.

References

Mehlmann J, Crawley M, Lundquist 4th J, Unwalla R, Harnish D, Evans M . Pyrrole[2,3-d]azepino compounds as agonists of the farnesoid X receptor (FXR). Bioorg Med Chem Lett. 2009; 19(18):5289-92. DOI: 10.1016/j.bmcl.2009.07.148. View

Agellon L, Walsh A, Hayek T, Moulin P, Jiang X, Shelanski S . Reduced high density lipoprotein cholesterol in human cholesteryl ester transfer protein transgenic mice. J Biol Chem. 1991; 266(17):10796-801. View

Inagaki T, Choi M, Moschetta A, Peng L, Cummins C, McDonald J . Fibroblast growth factor 15 functions as an enterohepatic signal to regulate bile acid homeostasis. Cell Metab. 2005; 2(4):217-25. DOI: 10.1016/j.cmet.2005.09.001. View

Jiang X, Agellon L, Walsh A, Breslow J, Tall A . Dietary cholesterol increases transcription of the human cholesteryl ester transfer protein gene in transgenic mice. Dependence on natural flanking sequences. J Clin Invest. 1992; 90(4):1290-5. PMC: 443172. DOI: 10.1172/JCI115993. View

Miettinen T, AHRENS Jr E, Grundy S . QUANTITATIVE ISOLATION AND GAS--LIQUID CHROMATOGRAPHIC ANALYSIS OF TOTAL DIETARY AND FECAL NEUTRAL STEROIDS. J Lipid Res. 1965; 6:411-24. View

Gardes C, Blum D, Bleicher K, Chaput E, Ebeling M, Hartman P . Studies in mice, hamsters, and rats demonstrate that repression of hepatic apoA-I expression by taurocholic acid in mice is not mediated by the farnesoid-X-receptor. J Lipid Res. 2011; 52(6):1188-1199. PMC: 3090240. DOI: 10.1194/jlr.M012542. View

Goodwin B, Jones S, Price R, Watson M, McKee D, Moore L . A regulatory cascade of the nuclear receptors FXR, SHP-1, and LRH-1 represses bile acid biosynthesis. Mol Cell. 2000; 6(3):517-26. DOI: 10.1016/s1097-2765(00)00051-4. View

Arai T, Wang N, Bezouevski M, Welch C, Tall A . Decreased atherosclerosis in heterozygous low density lipoprotein receptor-deficient mice expressing the scavenger receptor BI transgene. J Biol Chem. 1999; 274(4):2366-71. DOI: 10.1074/jbc.274.4.2366. View

Willson T, Jones S, Moore J, Kliewer S . Chemical genomics: functional analysis of orphan nuclear receptors in the regulation of bile acid metabolism. Med Res Rev. 2001; 21(6):513-22. DOI: 10.1002/med.1023. View

10.

Porez G, Prawitt J, Gross B, Staels B . Bile acid receptors as targets for the treatment of dyslipidemia and cardiovascular disease. J Lipid Res. 2012; 53(9):1723-37. PMC: 3413216. DOI: 10.1194/jlr.R024794. View

11.

Yu L, Gupta S, Xu F, Liverman A, Moschetta A, Mangelsdorf D . Expression of ABCG5 and ABCG8 is required for regulation of biliary cholesterol secretion. J Biol Chem. 2004; 280(10):8742-7. DOI: 10.1074/jbc.M411080200. View

12.

Lu T, Makishima M, REPA J, Schoonjans K, Kerr T, Auwerx J . Molecular basis for feedback regulation of bile acid synthesis by nuclear receptors. Mol Cell. 2000; 6(3):507-15. DOI: 10.1016/s1097-2765(00)00050-2. View

13.

Liang H, Chaparro-Riggers J, Strop P, Geng T, Sutton J, Tsai D . Proprotein convertase substilisin/kexin type 9 antagonism reduces low-density lipoprotein cholesterol in statin-treated hypercholesterolemic nonhuman primates. J Pharmacol Exp Ther. 2011; 340(2):228-36. DOI: 10.1124/jpet.111.187419. View

14.

Guo G, Santamarina-Fojo S, Akiyama T, Amar M, Paigen B, Brewer Jr B . Effects of FXR in foam-cell formation and atherosclerosis development. Biochim Biophys Acta. 2006; 1761(12):1401-9. PMC: 1751860. DOI: 10.1016/j.bbalip.2006.09.018. View

15.

Grundy S, AHRENS Jr E, Miettinen T . QUANTITATIVE ISOLATION AND GAS--LIQUID CHROMATOGRAPHIC ANALYSIS OF TOTAL FECAL BILE ACIDS. J Lipid Res. 1965; 6:397-410. View

16.

deGoma E, Rader D . Novel HDL-directed pharmacotherapeutic strategies. Nat Rev Cardiol. 2011; 8(5):266-77. PMC: 3315102. DOI: 10.1038/nrcardio.2010.200. View

17.

Zhang Y, Yin L, Anderson J, Ma H, Gonzalez F, Willson T . Identification of novel pathways that control farnesoid X receptor-mediated hypocholesterolemia. J Biol Chem. 2009; 285(5):3035-43. PMC: 2823426. DOI: 10.1074/jbc.M109.083899. View

18.

Kozarsky K, Donahee M, Glick J, Krieger M, Rader D . Gene transfer and hepatic overexpression of the HDL receptor SR-BI reduces atherosclerosis in the cholesterol-fed LDL receptor-deficient mouse. Arterioscler Thromb Vasc Biol. 2000; 20(3):721-7. DOI: 10.1161/01.atv.20.3.721. View

19.

Crawley M . Farnesoid X receptor modulators: a patent review. Expert Opin Ther Pat. 2010; 20(8):1047-57. DOI: 10.1517/13543776.2010.496777. View

20.

Cariou B, van Harmelen K, Duran-Sandoval D, van Dijk T, Grefhorst A, Abdelkarim M . The farnesoid X receptor modulates adiposity and peripheral insulin sensitivity in mice. J Biol Chem. 2006; 281(16):11039-49. DOI: 10.1074/jbc.M510258200. View