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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

Effect of DMHCA on hepatic fatty acid composition. C57Bl/6 mice were fed chow diet (A) or Western type diet (WTD) (B) (containing 80 mg DMHCA/kg body weight/day) for 15 days. 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.
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fig3: Effect of DMHCA on hepatic fatty acid composition. C57Bl/6 mice were fed chow diet (A) or Western type diet (WTD) (B) (containing 80 mg DMHCA/kg body weight/day) for 15 days. 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.

Mentions: To check whether a treatment longer than 4 days or WTD affects lipid parameters, male C57Bl/6 mice were fed chow or WTD ± 80 mg DMHCA/kg body weight/day for 15 days. Plasma TG concentrations were not significantly altered by DMHCA on both diets suggesting that a high dose of DMHCA fed for more than 2 weeks does not induce hypertriglyceridemia in wild-type animals (Table 1). Interestingly, plasma TC levels were significantly reduced by 32% in mice fed chow diet plus DMHCA but remained unchanged in mice fed WTD plus DMHCA when compared with controls. Hepatic TC concentrations were markedly decreased on both diets by DMHCA (54% and 56%, respectively). In contrast, hepatic TG levels were not changed by DMHCA in WTD, but were significantly increased by 2.4-fold by DMHCA in chow diet. Plasma AST levels were slightly but not significantly increased on chow diet plus DMHCA and unaltered by DMHCA in WTD-fed animals (Table 1). Oil Red O staining of liver sections from DMHCA-treated mice revealed macroscopically no differences in lipid accumulation upon the absence or presence of DMHCA in both diets, while T0901317 treatment resulted in severe steatosis with enlarged lipid droplets on both diets (see supplementary Figure I). Because we found slightly increased TG levels in DMHCA-treated livers on chow diet, we checked the hepatic fatty acid composition in the TG fraction, which was changed upon high DMHCA concentrations in the chow diet. Oleate (C18:1), palmitate (C16:0), linoleate (C18:2), and stearate (C16:1) were significantly increased (Fig. 3A). No alterations were observed in mice fed WTD plus DMHCA compared with WTD alone (Fig. 3B).


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. C57Bl/6 mice were fed chow diet (A) or Western type diet (WTD) (B) (containing 80 mg DMHCA/kg body weight/day) for 15 days. 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.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig3: Effect of DMHCA on hepatic fatty acid composition. C57Bl/6 mice were fed chow diet (A) or Western type diet (WTD) (B) (containing 80 mg DMHCA/kg body weight/day) for 15 days. 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.
Mentions: To check whether a treatment longer than 4 days or WTD affects lipid parameters, male C57Bl/6 mice were fed chow or WTD ± 80 mg DMHCA/kg body weight/day for 15 days. Plasma TG concentrations were not significantly altered by DMHCA on both diets suggesting that a high dose of DMHCA fed for more than 2 weeks does not induce hypertriglyceridemia in wild-type animals (Table 1). Interestingly, plasma TC levels were significantly reduced by 32% in mice fed chow diet plus DMHCA but remained unchanged in mice fed WTD plus DMHCA when compared with controls. Hepatic TC concentrations were markedly decreased on both diets by DMHCA (54% and 56%, respectively). In contrast, hepatic TG levels were not changed by DMHCA in WTD, but were significantly increased by 2.4-fold by DMHCA in chow diet. Plasma AST levels were slightly but not significantly increased on chow diet plus DMHCA and unaltered by DMHCA in WTD-fed animals (Table 1). Oil Red O staining of liver sections from DMHCA-treated mice revealed macroscopically no differences in lipid accumulation upon the absence or presence of DMHCA in both diets, while T0901317 treatment resulted in severe steatosis with enlarged lipid droplets on both diets (see supplementary Figure I). Because we found slightly increased TG levels in DMHCA-treated livers on chow diet, we checked the hepatic fatty acid composition in the TG fraction, which was changed upon high DMHCA concentrations in the chow diet. Oleate (C18:1), palmitate (C16:0), linoleate (C18:2), and stearate (C16:1) were significantly increased (Fig. 3A). No alterations were observed in mice fed WTD plus DMHCA compared with WTD alone (Fig. 3B).

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