Synthetic LXR agonist attenuates plaque formation in apoE-/- mice without inducing liver steatosis and hypertriglyceridemia

被引：114

作者：

Kratzer, Adelheid ^{[1
,2
]}

Buchebner, Marlene ^{[1
]}

Pfeifer, Thomas ^{[1
]}

Becker, Tatjana M. ^{[1
]}

Uray, Georg ^{[5
]}

Miyazaki, Makoto ^{[2
]}

Miyazaki-Anzai, Shinobu ^{[2
]}

Ebner, Birgit ^{[6
]}

Chandak, Prakash G. ^{[1
]}

Kadam, Rajendra S. ^{[3
]}

Calayir, Emine ^{[1
]}

Rathke, Nora ^{[1
]}

Ahammer, Helmut ^{[7
]}

Radovic, Branislav ^{[1
]}

Trauner, Michael ^{[8
]}

Hoefler, Gerald ^{[9
]}

Kompella, Uday B. ^{[4
]}

Fauler, Guenter ^{[10
]}

Levi, Moshe ^{[2
]}

Levak-Frank, Sanja ^{[1
]}

Kostner, Gerhard M. ^{[1
]}

Kratky, Dagmar ^{[1
]}

机构：

[1] Med Univ Graz, Ctr Mol Med, Inst Mol Biol & Biochem, A-8010 Graz, Austria

[2] Univ Colorado, Hlth Sci Ctr, Div Renal Dis & Hypertens, Denver, CO 80262 USA

[3] Univ Colorado, Hlth Sci Ctr, Dept Pharmaceut Sci, Denver, CO 80262 USA

[4] Univ Colorado, Hlth Sci Ctr, Dept Ophthalmol, Denver, CO 80262 USA

[5] Graz Univ, Inst Chem, A-8010 Graz, Austria

[6] Med Univ Graz, Med Res Ctr, A-8010 Graz, Austria

[7] Med Univ Graz, Inst Biophys, A-8010 Graz, Austria

[8] Med Univ Graz, Dept Internal Med, Div Gastroenterol & Hepatol, A-8036 Graz, Austria

[9] Med Univ Graz, Inst Pathol, A-8036 Graz, Austria

[10] Med Univ Graz, Clin Inst Med & Chem Lab Diagnost, A-8036 Graz, Austria

来源：

JOURNAL OF LIPID RESEARCH | 2009年 / 50卷 / 02期

基金：

奥地利科学基金会;

关键词：

atherogenesis; liver X receptor; cholesterol catabolism; ABC transporter; gene expression; ELEMENT-BINDING PROTEIN; PLASMA HDL CHOLESTEROL; NUCLEAR RECEPTOR LXR; X-RECEPTOR; CELLULAR CHOLESTEROL; TRANSCRIPTION FACTOR; DIETARY-CHOLESTEROL; OXYSTEROL RECEPTORS; GENE-EXPRESSION; LIGAND;

D O I：

10.1194/jlr.M800376-JLR200

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Liver X receptors (LXRs) are important regulators of cholesterol and lipid metabolism. LXR agonists have been shown to limit the cellular cholesterol content by inducing reverse cholesterol transport, increasing bile acid production, and inhibiting intestinal cholesterol absorption. Most of them, however, also increase lipogenesis via sterol regulatory element-binding protein-1c (SREBP1c) and carbohydrate response element-binding protein activation resulting in hypertriglyceridemia and liver steatosis. We report on the antiatherogenic properties of the steroidal liver X receptor agonist N,N-dimethyl-3 beta-hydroxy-cholenamide (DMHCA) in apolipoprotein E (apoE)-deficient mice. Long-term administration of DMHCA (11 weeks) significantly reduced lesion formation in male and female apoE-null mice. Notably, DMHCA neither increased hepatic triglyceride (TG) levels in male nor female apoE-deficient mice. ATP binding cassette transporter A1 and G1 and cholesterol 7 alpha-hydroxylase mRNA abundances were increased, whereas SREBP1c mRNA expression was unchanged in liver, and even decreased in macrophages and intestine. Short-term treatment revealed even higher changes on mRNA regulation. Our data provide evidence that DMHCA is a strong candidate as therapeutic agent for the treatment or prevention of atherosclerosis, circumventing the negative side effects of other LXR agonists. - Kratzer, A., M. Buchebner, T. Pfeifer, T. M. Becker, G. Uray, M. Miyazaki, S. Miyazaki-Anzai, B. Ebner, P. G. Chandak, R. S. Kadam, E. Calayir, N. Rathke, H. Ahammer, B. Radovic, M. Trauner, G. Hoefler, U. B. Kompella, G. Fauler, M. Levi, S. Levak-Frank, G. M. Kostner, and D. Kratky. Synthetic LXR agonist attenuates plaque formation in apoE-/- mice without inducing liver steatosis and hypertriglyceridemia. J. Lipid Res. 2009. 50: 312-326.

引用

页码：312 / 326

页数：15

共 38 条

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