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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

En face and aortic root section analysis of atherosclerosis in male apoE-deficient mice fed WTD ± DMHCA (8 mg/kg body weight/day) for 11 weeks. A: Representative staining of aorta and aortic valves with Oil Red O and MOMA-2 antibody. Lesions in aortic valves were analyzed in male (n = 6) (B) and female (n = 6) (C) apoE-deficient mice. Box plot graphics of en face analysis of male (n = 6) (D) and female (n = 7) (E) apoE-deficient mice. * P < 0.05; *** P ≤ 0.001.
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fig7: En face and aortic root section analysis of atherosclerosis in male apoE-deficient mice fed WTD ± DMHCA (8 mg/kg body weight/day) for 11 weeks. A: Representative staining of aorta and aortic valves with Oil Red O and MOMA-2 antibody. Lesions in aortic valves were analyzed in male (n = 6) (B) and female (n = 6) (C) apoE-deficient mice. Box plot graphics of en face analysis of male (n = 6) (D) and female (n = 7) (E) apoE-deficient mice. * P < 0.05; *** P ≤ 0.001.

Mentions: To examine the impact of DMHCA on atherogenesis in apoE-deficient mice, atherosclerotic lesions were evaluated by aortic valve section and en face analyses after 11 weeks on WTD in the absence or presence of DMHCA (Fig. 7). Mice receiving 8 mg DMHCA/kg body weight/day showed a decrease in average lesion area compared with controls by both en face and aortic valve section analysis. Immunohistochemical staining of macrophages in the aortic valves with a macrophage-specific anti-MOMA-2 antibody and Oil Red O staining of lipids demonstrated that lipids colocalize with macrophages and are more abundant in control apoE-deficient mice (Fig. 7A). Quantification of Oil Red O-stained aortic valve sections revealed that treatment with DMHCA resulted in a significant 45.9% and 48.4% decrease in lesion area in male (Fig. 7B) and female (Fig. 7C) apoE-deficient mice when compared with controls. To further document positive effects of DMHCA on atherosclerosis, Oil Red O-stained lesions in en face preparations of aortas were quantified. Treatment with DMHCA led to a significant reduction in lesion area of male and female apoE-deficient mice compared with controls (27.7% and 29.5%, respectively) (Fig. 7D, E).


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)

En face and aortic root section analysis of atherosclerosis in male apoE-deficient mice fed WTD ± DMHCA (8 mg/kg body weight/day) for 11 weeks. A: Representative staining of aorta and aortic valves with Oil Red O and MOMA-2 antibody. Lesions in aortic valves were analyzed in male (n = 6) (B) and female (n = 6) (C) apoE-deficient mice. Box plot graphics of en face analysis of male (n = 6) (D) and female (n = 7) (E) apoE-deficient mice. * P < 0.05; *** P ≤ 0.001.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig7: En face and aortic root section analysis of atherosclerosis in male apoE-deficient mice fed WTD ± DMHCA (8 mg/kg body weight/day) for 11 weeks. A: Representative staining of aorta and aortic valves with Oil Red O and MOMA-2 antibody. Lesions in aortic valves were analyzed in male (n = 6) (B) and female (n = 6) (C) apoE-deficient mice. Box plot graphics of en face analysis of male (n = 6) (D) and female (n = 7) (E) apoE-deficient mice. * P < 0.05; *** P ≤ 0.001.
Mentions: To examine the impact of DMHCA on atherogenesis in apoE-deficient mice, atherosclerotic lesions were evaluated by aortic valve section and en face analyses after 11 weeks on WTD in the absence or presence of DMHCA (Fig. 7). Mice receiving 8 mg DMHCA/kg body weight/day showed a decrease in average lesion area compared with controls by both en face and aortic valve section analysis. Immunohistochemical staining of macrophages in the aortic valves with a macrophage-specific anti-MOMA-2 antibody and Oil Red O staining of lipids demonstrated that lipids colocalize with macrophages and are more abundant in control apoE-deficient mice (Fig. 7A). Quantification of Oil Red O-stained aortic valve sections revealed that treatment with DMHCA resulted in a significant 45.9% and 48.4% decrease in lesion area in male (Fig. 7B) and female (Fig. 7C) apoE-deficient mice when compared with controls. To further document positive effects of DMHCA on atherosclerosis, Oil Red O-stained lesions in en face preparations of aortas were quantified. Treatment with DMHCA led to a significant reduction in lesion area of male and female apoE-deficient mice compared with controls (27.7% and 29.5%, respectively) (Fig. 7D, E).

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