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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

Liver analyses of C57Bl/6 mice fed chow diet or WTD ± T0901317 or DMHCA (80 mg/kg body weight/day) for 15 days. Real-time PCR expression ratios upon liver X receptors (LXR) agonist treatment in chow (A) and WTD (B) fed mice including hypoxanthine guanine phosphoribosyl transferase (HPRT) normalization were calculated by pairwise fixed reallocation test. Controls fed chow or WTD without LXR ligand were arbitrarily set to 1. Data are expressed as mean values ± SD; n = 8 performed in duplicate. * P < 0.05; ** P ≤ 0.01; *** P ≤ 0.001.
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fig4: Liver analyses of C57Bl/6 mice fed chow diet or WTD ± T0901317 or DMHCA (80 mg/kg body weight/day) for 15 days. Real-time PCR expression ratios upon liver X receptors (LXR) agonist treatment in chow (A) and WTD (B) fed mice including hypoxanthine guanine phosphoribosyl transferase (HPRT) normalization were calculated by pairwise fixed reallocation test. Controls fed chow or WTD without LXR ligand were arbitrarily set to 1. Data are expressed as mean values ± SD; n = 8 performed in duplicate. * P < 0.05; ** P ≤ 0.01; *** P ≤ 0.001.

Mentions: Target gene expression levels in livers of C57Bl/6 mice fed chow or WTD ± T0901317 or DMHCA (80 mg/kg body weight/day) for 15 days were analyzed by real time PCR. In chow diet, treatment with DMHCA led to a significant 2.5-fold increase of CYP7A1 mRNA expression (Fig. 4A). Additionally, the expression levels of ABCA1, ABCG1, ABCG5, and ABCG8 were significantly increased by 1.9-, 2.1-, 3.5- and 2.8-fold, respectively. Hepatic SREBP1c, fatty acid synthase (FAS) and ChREBP mRNA quantities were unaltered upon DMHCA treatment. T0901317 in chow diet resulted in more pronounced increase of CYP7A1, ABCA1, ABCG1, and ABCG5/G8 mRNA expression compared with controls, but also enhanced SREBP1c, FAS, and ChREBP mRNA by 4.7-, 3.4-, and 1.3-fold, respectively (Fig. 4A). Similar real-time PCR results were obtained when mRNA levels were determined from livers of mice fed WTD plus the LXR agonists. Both ligands significantly increased CYP7A1 and ABCG8 mRNA, only T0901317 resulted in an increase in ABCG1 and ABCG5 mRNA, while ABCA1 mRNA was unaltered by T0901317 and DMHCA treatment. While T0901317 significantly increased SREBP1c and FAS by 3.4- and 47.3-fold, respectively, DMHCA did not alter SREBP1c mRNA expression. While FAS mRNA was significantly increased by 2.7-fold, ChREBP was significantly decreased upon DMHCA treatment by 47%. We also analyzed ABCA1, ABCG1, ABCG5, and ABCG8 mRNA levels in ileum of T0901317 and DMHCA in chow diet and found these ABC transporters significantly increased by both ligands; again the upregulation was higher by T0901317 treatment (see supplementary Figure II).


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)

Liver analyses of C57Bl/6 mice fed chow diet or WTD ± T0901317 or DMHCA (80 mg/kg body weight/day) for 15 days. Real-time PCR expression ratios upon liver X receptors (LXR) agonist treatment in chow (A) and WTD (B) fed mice including hypoxanthine guanine phosphoribosyl transferase (HPRT) normalization were calculated by pairwise fixed reallocation test. Controls fed chow or WTD without LXR ligand were arbitrarily set to 1. Data are expressed as mean values ± SD; n = 8 performed in duplicate. * P < 0.05; ** P ≤ 0.01; *** P ≤ 0.001.
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2636920&req=5

fig4: Liver analyses of C57Bl/6 mice fed chow diet or WTD ± T0901317 or DMHCA (80 mg/kg body weight/day) for 15 days. Real-time PCR expression ratios upon liver X receptors (LXR) agonist treatment in chow (A) and WTD (B) fed mice including hypoxanthine guanine phosphoribosyl transferase (HPRT) normalization were calculated by pairwise fixed reallocation test. Controls fed chow or WTD without LXR ligand were arbitrarily set to 1. Data are expressed as mean values ± SD; n = 8 performed in duplicate. * P < 0.05; ** P ≤ 0.01; *** P ≤ 0.001.
Mentions: Target gene expression levels in livers of C57Bl/6 mice fed chow or WTD ± T0901317 or DMHCA (80 mg/kg body weight/day) for 15 days were analyzed by real time PCR. In chow diet, treatment with DMHCA led to a significant 2.5-fold increase of CYP7A1 mRNA expression (Fig. 4A). Additionally, the expression levels of ABCA1, ABCG1, ABCG5, and ABCG8 were significantly increased by 1.9-, 2.1-, 3.5- and 2.8-fold, respectively. Hepatic SREBP1c, fatty acid synthase (FAS) and ChREBP mRNA quantities were unaltered upon DMHCA treatment. T0901317 in chow diet resulted in more pronounced increase of CYP7A1, ABCA1, ABCG1, and ABCG5/G8 mRNA expression compared with controls, but also enhanced SREBP1c, FAS, and ChREBP mRNA by 4.7-, 3.4-, and 1.3-fold, respectively (Fig. 4A). Similar real-time PCR results were obtained when mRNA levels were determined from livers of mice fed WTD plus the LXR agonists. Both ligands significantly increased CYP7A1 and ABCG8 mRNA, only T0901317 resulted in an increase in ABCG1 and ABCG5 mRNA, while ABCA1 mRNA was unaltered by T0901317 and DMHCA treatment. While T0901317 significantly increased SREBP1c and FAS by 3.4- and 47.3-fold, respectively, DMHCA did not alter SREBP1c mRNA expression. While FAS mRNA was significantly increased by 2.7-fold, ChREBP was significantly decreased upon DMHCA treatment by 47%. We also analyzed ABCA1, ABCG1, ABCG5, and ABCG8 mRNA levels in ileum of T0901317 and DMHCA in chow diet and found these ABC transporters significantly increased by both ligands; again the upregulation was higher by T0901317 treatment (see supplementary Figure II).

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