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

ABSTRACT: 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-3beta-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 7alpha-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.

SUBMITTER: Kratzer A

PROVIDER: S-EPMC2636920 | biostudies-literature | 2009 Feb

REPOSITORIES: biostudies-literature

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

Kratzer Adelheid A Buchebner Marlene M Pfeifer Thomas T Becker Tatjana M TM Uray Georg G Miyazaki Makoto M Miyazaki-Anzai Shinobu S Ebner Birgit B Chandak Prakash G PG Kadam Rajendra S RS Calayir Emine E Rathke Nora N Ahammer Helmut H Radovic Branislav B Trauner Michael M Hoefler Gerald G Kompella Uday B UB Fauler Guenter G Levi Moshe M Levak-Frank Sanja S Kostner Gerhard M GM Kratky Dagmar D

Journal of lipid research 20080923 2

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 ste ...[more]

PMID: 18812595

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Project description:BACKGROUND AND PURPOSE:Atherosclerosis is a chronic inflammatory disease, and retinoid X receptor-? (RXR?) is an intriguing anti-atherosclerosis target. This study investigated whether and how an RXR? modulator, K-80003, derived from a non-steroidal anti-inflammatory drug attenuates atherosclerotic plaque progression and destabilization. EXPERIMENTAL APPROACH:Our previously established ApoE-/- mouse model of carotid vulnerable plaque progression was treated with K-80003 or vehicle for 4 or 8 weeks. Samples of carotid arteries and serum were collected to determine atherosclerotic lesion size, histological features, expression of related proteins, and lipid profiles. In vitro studies were carried out in 7-ketocholesterol (7-KC)-stimulated macrophages treated with or without K-80003. KEY RESULTS:K-80003 significantly reduced lesion size, plaque rupture, macrophage infiltration, and inflammatory cytokine levels. Plaque macrophages positive for nuclear p65 (RelA) NF-?B subunit were markedly reduced after K-80003 treatment. Also, K-80003 treatment inhibited 7-KC-induced p65 nuclear translocation, I?B? degradation, and transcription of NF-?B target genes. In addition, K-80003 inhibited NF-?B pathway mainly through the reduction of p62/sequestosome 1 (SQSTM1), probably due to promotion of autophagic flux by K-80003. Mechanistically, cytoplasmic localization of RXR? was associated with decreased autophagic flux. Increasing cytoplasmic RXR? expression by overexpression of RXR?/385 mutant decreased autophagic flux in RAW264.7 cells. Finally, K-80003 strongly inhibited 7-KC-induced RXR? cytoplasmic translocation. CONCLUSIONS AND IMPLICATIONS:K-80003 suppressed atherosclerotic plaque progression and destabilization by promoting macrophage autophagic flux and consequently inhibited the p62/SQSTM1-mediated NF-?B proinflammatory pathway. Thus, targeting RXR?-mediated autophagy-inflammation axis by its noncanonical modulator may represent a promising strategy to treat atherosclerosis.

Dataset Information

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

Publications

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

Similar Datasets

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