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

Kratzer A, Buchebner M, Pfeifer T, Becker TM, Uray G, Miyazaki M, Miyazaki-Anzai S, Ebner B, Chandak PG, Kadam RS, Calayir E, Rathke N, Ahammer H, Radovic B, Trauner M, Hoefler G, Kompella UB, Fauler G, Levi M, Levak-Frank S, Kostner GM, Kratky D - J. Lipid Res. (2008)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Institute of Molecular Biology and Biochemistry, Center of Molecular Medicine, Medical University of Graz, Harrachgasse 21/3, 8010 Graz, Austria.

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- 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.

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Related in: MedlinePlus

N,N-dimethyl-3β-hydroxy-cholenamide (DMHCA) induces ATP-binding cassette (ABC)A1 mRNA expression in macrophages and foam cells. Peritoneal macrophages (MPM) from C57Bl/6 mice were isolated and incubated ± 50 μg/ml aggregated LDL for 24 h in the absence or presence of 2.5 μM DMHCA. ABCA1 mRNA expression ratio in MPM and foam cells plus DMHCA including cyclophilin A normalization was calculated by pairwise fixed reallocation test relative to control MPM and foam cells (arbitrarily set to 1). Data are expressed as mean ± SD. ** P ≤ 0.01; *** P ≤ 0.001.
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fig1: N,N-dimethyl-3β-hydroxy-cholenamide (DMHCA) induces ATP-binding cassette (ABC)A1 mRNA expression in macrophages and foam cells. Peritoneal macrophages (MPM) from C57Bl/6 mice were isolated and incubated ± 50 μg/ml aggregated LDL for 24 h in the absence or presence of 2.5 μM DMHCA. ABCA1 mRNA expression ratio in MPM and foam cells plus DMHCA including cyclophilin A normalization was calculated by pairwise fixed reallocation test relative to control MPM and foam cells (arbitrarily set to 1). Data are expressed as mean ± SD. ** P ≤ 0.01; *** P ≤ 0.001.

Mentions: MPM isolated from C57Bl/6 mice and foam cells were incubated in the absence or presence of 2.5 μM DMHCA for 24 h. As expected, DMHCA was found to stimulate ABCA1 mRNA expression in MPM and in aggregated LDL-laden foam cells in vitro by 7.0- and 4.8-fold, respectively, compared with untreated macrophages and foam cells (Fig. 1).


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

Kratzer A, Buchebner M, Pfeifer T, Becker TM, Uray G, Miyazaki M, Miyazaki-Anzai S, Ebner B, Chandak PG, Kadam RS, Calayir E, Rathke N, Ahammer H, Radovic B, Trauner M, Hoefler G, Kompella UB, Fauler G, Levi M, Levak-Frank S, Kostner GM, Kratky D - J. Lipid Res. (2008)

N,N-dimethyl-3β-hydroxy-cholenamide (DMHCA) induces ATP-binding cassette (ABC)A1 mRNA expression in macrophages and foam cells. Peritoneal macrophages (MPM) from C57Bl/6 mice were isolated and incubated ± 50 μg/ml aggregated LDL for 24 h in the absence or presence of 2.5 μM DMHCA. ABCA1 mRNA expression ratio in MPM and foam cells plus DMHCA including cyclophilin A normalization was calculated by pairwise fixed reallocation test relative to control MPM and foam cells (arbitrarily set to 1). Data are expressed as mean ± SD. ** P ≤ 0.01; *** P ≤ 0.001.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2636920&req=5

fig1: N,N-dimethyl-3β-hydroxy-cholenamide (DMHCA) induces ATP-binding cassette (ABC)A1 mRNA expression in macrophages and foam cells. Peritoneal macrophages (MPM) from C57Bl/6 mice were isolated and incubated ± 50 μg/ml aggregated LDL for 24 h in the absence or presence of 2.5 μM DMHCA. ABCA1 mRNA expression ratio in MPM and foam cells plus DMHCA including cyclophilin A normalization was calculated by pairwise fixed reallocation test relative to control MPM and foam cells (arbitrarily set to 1). Data are expressed as mean ± SD. ** P ≤ 0.01; *** P ≤ 0.001.
Mentions: MPM isolated from C57Bl/6 mice and foam cells were incubated in the absence or presence of 2.5 μM DMHCA for 24 h. As expected, DMHCA was found to stimulate ABCA1 mRNA expression in MPM and in aggregated LDL-laden foam cells in vitro by 7.0- and 4.8-fold, respectively, compared with untreated macrophages and foam cells (Fig. 1).

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Institute of Molecular Biology and Biochemistry, Center of Molecular Medicine, Medical University of Graz, Harrachgasse 21/3, 8010 Graz, Austria.

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- 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.

Show MeSH
Related in: MedlinePlus