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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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Effect of DMHCA on hepatic fatty acid composition in apoE-deficient mice. Male apoE-deficient mice were fed chow diet ± DMHCA (80 mg/kg body weight/day) for 4 days (A) or WTD ± DMHCA (8 mg/kg body weight/day) for 15 days (B). Fatty acid composition in the livers was determined by gas chromatography after methylation using heptadecanoic acid as internal standard. Data represent the mean values ± SD; n = 8. * P < 0.05; ** P ≤ 0.01; ***P ≤ 0.001.
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fig10: Effect of DMHCA on hepatic fatty acid composition in apoE-deficient mice. Male apoE-deficient mice were fed chow diet ± DMHCA (80 mg/kg body weight/day) for 4 days (A) or WTD ± DMHCA (8 mg/kg body weight/day) for 15 days (B). Fatty acid composition in the livers was determined by gas chromatography after methylation using heptadecanoic acid as internal standard. Data represent the mean values ± SD; n = 8. * P < 0.05; ** P ≤ 0.01; ***P ≤ 0.001.

Mentions: To examine whether DMHCA treatment affects plasma and hepatic lipid parameters in apoE-deficient animals in a short-term treatment, male mice were fed chow ± 80 mg DMHCA/kg body weight/day for 4 days. In addition, we wanted to check whether WTD fed for a shorter time (15 days) than 11 weeks ± 8 mg DMHCA/kg body weight/day has an effect on lipid parameters. We found that plasma TG and TC concentrations were not significantly changed upon DMHCA treatment on both diets, confirming our data that DMHCA does not induce hypertriglyceridemia in apoE- mice (Table 3). Following treatment with DMHCA, there were no changes in liver TC content. Liver TG levels were significantly decreased in mice fed a chow diet plus DMHCA (Fig. 10A), and they were not changed in mice fed a WTD plus DMHCA (Fig. 10B). Plasma AST levels were similar in all animals. Furthermore, the hepatic fatty acid composition in the TG fraction especially oleate (C18:1), palmitate (C16:0), and linoleate (C18:2) were significantly decreased (Fig. 10A). In contrast, no alterations in the hepatic fatty acid composition was observed in mice fed WTD plus DMHCA compared with WTD alone (Fig. 10B). However, when mice were fed WTD and high concentration of DMHCA (80 mg/kg body weight/day) for 4 days, this also resulted in a drastic decrease of all measured fatty acids, while no changes in fatty acid composition were observed when mice were fed chow diet plus 8 mg DMHCA/kg body weight/day (data not shown). These data indicate that 8 mg/kg/day of DMHCA, which is sufficient to reduce atherosclerosis in apoE-deficient mice when fed for 11 weeks, does not affect hepatic fatty acid composition after 15 days, while 80 mg/kg/day significantly reduces fatty acid concentrations in the liver even after a 4 day treatment.


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)

Effect of DMHCA on hepatic fatty acid composition in apoE-deficient mice. Male apoE-deficient mice were fed chow diet ± DMHCA (80 mg/kg body weight/day) for 4 days (A) or WTD ± DMHCA (8 mg/kg body weight/day) for 15 days (B). Fatty acid composition in the livers was determined by gas chromatography after methylation using heptadecanoic acid as internal standard. Data represent the mean values ± SD; n = 8. * 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

fig10: Effect of DMHCA on hepatic fatty acid composition in apoE-deficient mice. Male apoE-deficient mice were fed chow diet ± DMHCA (80 mg/kg body weight/day) for 4 days (A) or WTD ± DMHCA (8 mg/kg body weight/day) for 15 days (B). Fatty acid composition in the livers was determined by gas chromatography after methylation using heptadecanoic acid as internal standard. Data represent the mean values ± SD; n = 8. * P < 0.05; ** P ≤ 0.01; ***P ≤ 0.001.
Mentions: To examine whether DMHCA treatment affects plasma and hepatic lipid parameters in apoE-deficient animals in a short-term treatment, male mice were fed chow ± 80 mg DMHCA/kg body weight/day for 4 days. In addition, we wanted to check whether WTD fed for a shorter time (15 days) than 11 weeks ± 8 mg DMHCA/kg body weight/day has an effect on lipid parameters. We found that plasma TG and TC concentrations were not significantly changed upon DMHCA treatment on both diets, confirming our data that DMHCA does not induce hypertriglyceridemia in apoE- mice (Table 3). Following treatment with DMHCA, there were no changes in liver TC content. Liver TG levels were significantly decreased in mice fed a chow diet plus DMHCA (Fig. 10A), and they were not changed in mice fed a WTD plus DMHCA (Fig. 10B). Plasma AST levels were similar in all animals. Furthermore, the hepatic fatty acid composition in the TG fraction especially oleate (C18:1), palmitate (C16:0), and linoleate (C18:2) were significantly decreased (Fig. 10A). In contrast, no alterations in the hepatic fatty acid composition was observed in mice fed WTD plus DMHCA compared with WTD alone (Fig. 10B). However, when mice were fed WTD and high concentration of DMHCA (80 mg/kg body weight/day) for 4 days, this also resulted in a drastic decrease of all measured fatty acids, while no changes in fatty acid composition were observed when mice were fed chow diet plus 8 mg DMHCA/kg body weight/day (data not shown). These data indicate that 8 mg/kg/day of DMHCA, which is sufficient to reduce atherosclerosis in apoE-deficient mice when fed for 11 weeks, does not affect hepatic fatty acid composition after 15 days, while 80 mg/kg/day significantly reduces fatty acid concentrations in the liver even after a 4 day treatment.

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