Abstract
Liver X receptor (LXR) agonists have the potential to treat atherosclerosis based on their ability to enhance reverse cholesterol transport. However, their side effects, such as induction of liver lipogenesis and triglyceridemia, may limit their pharmaceutical development. In contrast to the nonsteroidal LXR agonist N-(2,2,2-trifluoroethyl)-N-[4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl]-benzenesulfonamide (T0901317), 3α, 6α, 24-trihydroxy-24, 24-di(trifluoromethyl)-5β-cholane (ATI-829), a novel potent synthetic steroidal LXR agonist, was a poor inducer of sterol regulatory element-binding protein 1c expression in hepatoma HepG2 cells, whereas both compounds increased ABCA1 expression in macrophage THP-1 cells. In male low-density lipoprotein receptor-deficient mice, ATI-829 selectively activated LXR target gene expression in mouse intestines and macrophages but not in the liver. A significant increase in liver triglyceride and plasma triglyceriderich small very low-density lipoprotein (VLDL) was observed in T0901317 but not ATI-829-treated mice. Compared with vehicle-treated mice, atherosclerosis development was significantly inhibited in the innominate artery after treatment with either compound. However, in the aortic root, inhibition of atherosclerosis was only observed in the right (right coronary artery-associated sinus) but not the left coronary-related sinus (left coronary artery-associated sinus; LC) of mice treated with either compound. Lesions in the innominate artery were less complex after treatment with either compound and contained mostly macrophage foam cells. In contrast, LC lesions were more complex and had a large collagen-positive fibrous cap and less macrophage foam cell area after treatment with either compound. The T0901317-induced hypertriglyceridemia was accompanied by an increase in small triglyceride-rich VLDL that may influence LXR agonist-mediated antiatherosclerotic effects at certain vascular sites. ATI-829, by selectively activating LXR in certain tissues without inducing hypertriglyceridemia, is a good candidate for drug development.
Footnotes
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This research was partly supported by National Institutes of Health Grants AT00850 and CA58073 and funding from Anagen Therapeutics Inc.
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S.L. has a financial interest in Anagen Therapeutics Inc., which has licensed patents dealing with ATI-829.
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Liao S and Dai Q (2006) inventors; ARCH Development Corporation, assignee. Liver X receptor agonists. U.S. patent US7012069B2. 2006 Mar 14.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.108.142687.
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ABBREVIATIONS: LDL, low-density lipoprotein; CHD, coronary heart disease; apo, apolipoprotein; LXR, liver X receptor; HDL, high-density lipoprotein; ABC, ATP-binding cassette transporter; SREBP-1c, sterol regulatory element-binding protein 1c; FAS, fatty acid synthase; ACC, acetyl-coenzyme A carboxylase; ATI-829, 3α,6α,24-trihydroxy-24, 24-di(trifluoromethyl)-5β-cholane; LDLR-/-, LDL receptor deficient; T0901317, N-(2,2,2-trifluoroethyl)-N-[4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl]-benzenesulfonamide; 22(R)-HC, 22(R)-hydroxycholesterol; 24(S)-HC, 24(S)-hydroxycholesterol; 24(S), 25-EC, 24(S),25-epoxycholesterol; HEK, human embryonic kidney; FPLC, fast protein liquid chromatography; EM, electron microscopy; VLDL, very low-density lipoprotein; PCR, polymerase chain reaction; 36B4, acidic ribosomal phosphoprotein; LPL, lipoprotein lipase; LC, left coronary artery-associated sinus; RC, right coronary artery-associated sinus; NC, sinus not associated with a coronary artery.
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↵ The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.
- Received June 25, 2008.
- Accepted August 21, 2008.
- The American Society for Pharmacology and Experimental Therapeutics
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