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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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Regulation of LXR target mRNA levels in apoE-deficient mice by short-term administration of DMHCA. Male mice were fed chow diet ± DMHCA (80 mg/kg body weight/day) for 4 days (A–D) or WTD ± DMHCA (8 mg/kg body weight/day) for 15 days (E–H). Real-time PCR expression ratios in liver (A, E), aorta (B, F), MPM (C, G), and ileum (D, H) including HPRT or cyclophilin A normalization were calculated by pairwise fixed reallocation test. Controls fed diets without DMHCA were arbitrarily set to 1. Data are expressed as mean values from three samples performed in triplicate ± SD. * P < 0.05; ** P ≤ 0.01; *** P ≤ 0.001.
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fig9: Regulation of LXR target mRNA levels in apoE-deficient mice by short-term administration of DMHCA. Male mice were fed chow diet ± DMHCA (80 mg/kg body weight/day) for 4 days (A–D) or WTD ± DMHCA (8 mg/kg body weight/day) for 15 days (E–H). Real-time PCR expression ratios in liver (A, E), aorta (B, F), MPM (C, G), and ileum (D, H) including HPRT or cyclophilin A normalization were calculated by pairwise fixed reallocation test. Controls fed diets without DMHCA were arbitrarily set to 1. Data are expressed as mean values from three samples performed in triplicate ± SD. * P < 0.05; ** P ≤ 0.01; *** P ≤ 0.001.

Mentions: Finally, we determined the effects of short-term DMHCA administration on target gene expression in apoE-deficient mice. Mice were fed normal chow diet (in the absence or presence of 80 mg DMHCA/kg body weight/day) for 4 days or WTD (in the absence or presence of 8 mg DMHCA/kg body weight/day) for 15 days. In the liver, treatment with DMHCA resulted in a significant induction of CYP7A1 mRNA expression on both diets, while ABCG5 and ABCG8 were increased by DMHCA only in the chow diet (1.4- and 1.3-fold, respectively). ABCA1, LDLR, and HMGCR mRNA were not altered upon feeding both diets. SREBP1c decreased upon DMHCA feeding with the chow diet by 52% (Fig. 9A, E). In addition, we checked whether DMHCA had an influence on gene expression in the aortae. Administration of DMHCA to chow and WTD increased ABCA1 mRNA levels in the aortae by 1.4- and 1.7-fold, respectively, while ABCG1 was significantly elevated by DMHCA only in chow diet by 1.9-fold (Fig. 9B, F). Additionally, ABCA1 mRNA was found to be increased by DMHCA upon chow and WTD feeding (1.7- and 3.1-fold, respectively) (Fig. 9C, G). In the ileum, ABCA1, ABCG1, and ABCG5 were all increased upon DMHCA administration in the chow diet (2.7-, 1.9- and 1.3-fold, respectively) (Fig. 9D). While ABCA1 mRNA quantity was significantly 1.7-fold increased in mice fed WTD supplemented with DMHCA, no changes were observed in ABCG1 and ABCG5 mRNA levels (Fig. 9H). To summarize, all effects on mRNA expression levels were similar in apoE-deficient mice after short-time feeding of both diets with the high dose of DMHCA in chow diet resulting in higher and more significant changes.


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 in apoE-deficient mice by short-term administration of DMHCA. Male mice were fed chow diet ± DMHCA (80 mg/kg body weight/day) for 4 days (A–D) or WTD ± DMHCA (8 mg/kg body weight/day) for 15 days (E–H). Real-time PCR expression ratios in liver (A, E), aorta (B, F), MPM (C, G), and ileum (D, H) including HPRT or cyclophilin A normalization were calculated by pairwise fixed reallocation test. Controls fed diets without DMHCA were arbitrarily set to 1. Data are expressed as mean values from three samples performed in triplicate ± SD. * P < 0.05; ** P ≤ 0.01; *** P ≤ 0.001.
© Copyright Policy - open-access
Related In: Results  -  Collection

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fig9: Regulation of LXR target mRNA levels in apoE-deficient mice by short-term administration of DMHCA. Male mice were fed chow diet ± DMHCA (80 mg/kg body weight/day) for 4 days (A–D) or WTD ± DMHCA (8 mg/kg body weight/day) for 15 days (E–H). Real-time PCR expression ratios in liver (A, E), aorta (B, F), MPM (C, G), and ileum (D, H) including HPRT or cyclophilin A normalization were calculated by pairwise fixed reallocation test. Controls fed diets without DMHCA were arbitrarily set to 1. Data are expressed as mean values from three samples performed in triplicate ± SD. * P < 0.05; ** P ≤ 0.01; *** P ≤ 0.001.
Mentions: Finally, we determined the effects of short-term DMHCA administration on target gene expression in apoE-deficient mice. Mice were fed normal chow diet (in the absence or presence of 80 mg DMHCA/kg body weight/day) for 4 days or WTD (in the absence or presence of 8 mg DMHCA/kg body weight/day) for 15 days. In the liver, treatment with DMHCA resulted in a significant induction of CYP7A1 mRNA expression on both diets, while ABCG5 and ABCG8 were increased by DMHCA only in the chow diet (1.4- and 1.3-fold, respectively). ABCA1, LDLR, and HMGCR mRNA were not altered upon feeding both diets. SREBP1c decreased upon DMHCA feeding with the chow diet by 52% (Fig. 9A, E). In addition, we checked whether DMHCA had an influence on gene expression in the aortae. Administration of DMHCA to chow and WTD increased ABCA1 mRNA levels in the aortae by 1.4- and 1.7-fold, respectively, while ABCG1 was significantly elevated by DMHCA only in chow diet by 1.9-fold (Fig. 9B, F). Additionally, ABCA1 mRNA was found to be increased by DMHCA upon chow and WTD feeding (1.7- and 3.1-fold, respectively) (Fig. 9C, G). In the ileum, ABCA1, ABCG1, and ABCG5 were all increased upon DMHCA administration in the chow diet (2.7-, 1.9- and 1.3-fold, respectively) (Fig. 9D). While ABCA1 mRNA quantity was significantly 1.7-fold increased in mice fed WTD supplemented with DMHCA, no changes were observed in ABCG1 and ABCG5 mRNA levels (Fig. 9H). To summarize, all effects on mRNA expression levels were similar in apoE-deficient mice after short-time feeding of both diets with the high dose of DMHCA in chow diet resulting in higher and more significant changes.

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