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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

Regulation of LXR target mRNA levels after chronic administration of DMHCA. ApoE-deficient mice were fed WTD ± DMHCA (8 mg/kg body weight/day) for 11 weeks. Real-time PCR expression ratios in liver (A), peritoneal macrophages (MPM) (B), and ileum (C) including HPRT or cyclophilin A normalization were calculated by pairwise fixed reallocation test. Controls fed WTD were arbitrarily set to 1. Data are expressed as mean values ± SD; n = 3 performed in triplicate. * P < 0.05; ** P ≤ 0.01; *** P ≤ 0.001.
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fig8: Regulation of LXR target mRNA levels after chronic administration of DMHCA. ApoE-deficient mice were fed WTD ± DMHCA (8 mg/kg body weight/day) for 11 weeks. Real-time PCR expression ratios in liver (A), peritoneal macrophages (MPM) (B), and ileum (C) including HPRT or cyclophilin A normalization were calculated by pairwise fixed reallocation test. Controls fed WTD were arbitrarily set to 1. Data are expressed as mean values ± SD; n = 3 performed in triplicate. * P < 0.05; ** P ≤ 0.01; *** P ≤ 0.001.

Mentions: To elucidate the long-term effect of DMHCA administration on gene expression levels in apoE-deficient mice after 11 weeks on WTD with or without DMHCA, gene expression levels in liver, MPM, and small intestine were analyzed by real time PCR. In the liver, ABCG1 and CYP7A1 mRNA expression levels were significantly increased by 2.3- and 2.8-fold, respectively, whereas ABCA1, ABCG5, and ABCG8 mRNAs remained unchanged (Fig. 8A). Importantly, hepatic SREBP1c, FAS, and ChREBP mRNA expressions were not upregulated upon DMHCA treatment. These results together with unchanged hepatic TG concentrations corroborate our data that chronic DMHCA administration does not induce liver steatosis.


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)

Regulation of LXR target mRNA levels after chronic administration of DMHCA. ApoE-deficient mice were fed WTD ± DMHCA (8 mg/kg body weight/day) for 11 weeks. Real-time PCR expression ratios in liver (A), peritoneal macrophages (MPM) (B), and ileum (C) including HPRT or cyclophilin A normalization were calculated by pairwise fixed reallocation test. Controls fed WTD were arbitrarily set to 1. Data are expressed as mean values ± SD; n = 3 performed in triplicate. * P < 0.05; ** P ≤ 0.01; *** P ≤ 0.001.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig8: Regulation of LXR target mRNA levels after chronic administration of DMHCA. ApoE-deficient mice were fed WTD ± DMHCA (8 mg/kg body weight/day) for 11 weeks. Real-time PCR expression ratios in liver (A), peritoneal macrophages (MPM) (B), and ileum (C) including HPRT or cyclophilin A normalization were calculated by pairwise fixed reallocation test. Controls fed WTD were arbitrarily set to 1. Data are expressed as mean values ± SD; n = 3 performed in triplicate. * P < 0.05; ** P ≤ 0.01; *** P ≤ 0.001.
Mentions: To elucidate the long-term effect of DMHCA administration on gene expression levels in apoE-deficient mice after 11 weeks on WTD with or without DMHCA, gene expression levels in liver, MPM, and small intestine were analyzed by real time PCR. In the liver, ABCG1 and CYP7A1 mRNA expression levels were significantly increased by 2.3- and 2.8-fold, respectively, whereas ABCA1, ABCG5, and ABCG8 mRNAs remained unchanged (Fig. 8A). Importantly, hepatic SREBP1c, FAS, and ChREBP mRNA expressions were not upregulated upon DMHCA treatment. These results together with unchanged hepatic TG concentrations corroborate our data that chronic DMHCA administration does not induce liver steatosis.

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