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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 distribution of triglycerides and cholesterol in plasma lipoprotein fractions of apoE-deficient mice. Lipoprotein profile of plasma pools of five fasted female apoE-deficient mice fed WTD ± DMHCA (8 mg/kg body weight/day) for 11 weeks. Plasma lipoproteins were separated by fast protein liquid chromatography. TG (A) and TC (B) concentrations in each fraction were measured enzymatically.
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fig6: Effect of DMHCA on distribution of triglycerides and cholesterol in plasma lipoprotein fractions of apoE-deficient mice. Lipoprotein profile of plasma pools of five fasted female apoE-deficient mice fed WTD ± DMHCA (8 mg/kg body weight/day) for 11 weeks. Plasma lipoproteins were separated by fast protein liquid chromatography. TG (A) and TC (B) concentrations in each fraction were measured enzymatically.

Mentions: Because we observed beneficial effects of DMHCA in wild-type mice, we further investigated the effect of DMHCA on body weight and lipid parameters in apoE-deficient mice during a long-term treatment. For that purpose, animals were fed WTD with or without DMHCA (8 mg/kg body weight/day) for 11 weeks. Although the food intake was similar in the different groups, male and female mice fed WTD plus DMHCA showed slightly decreased body weight gain when compared with mice fed WTD without DMHCA, which reached significance in female mice after 8 weeks of treatment (Fig. 5A, B). Plasma TC and TG levels were determined biweekly in the fed state. While no significant differences were observed in plasma TC (Fig. 5C) and TG (Fig. 5E) concentrations in male mice, female mice showed a significant decrease in TC (Fig. 5D) and TG (Fig. 5F) levels. Similar changes in plasma lipid levels were observed when mice were fasted overnight before blood was taken after 11 weeks of feeding WTD plus DMHCA (Table 2). We found reduced plasma TG levels in male (140 ± 10 mg/dl) and female (163 ± 9 mg/dl) apoE-deficient mice compared with mice fed WTD alone (197 ± 26 and 220 ± 5 mg/dl, respectively), whereas TC concentrations were significantly decreased only in male (799 ± 65 mg/dl vs. 1131 ± 52 mg/dl) but not in female animals (587 ± 33 mg/dl vs. 638 ± 16 mg/dl, respectively). No significant changes were found in HDL cholesterol levels. Determination of plasma AST or ALT levels did not give reliable results due to lipemic samples. Yet we determined bilirubin concentrations and found that they were comparable upon all diets. Therefore, long-time treatment did not lead to liver damage in apoE-deficient mice. Additionally, hepatic TG concentrations were unaltered in male (15.6 ± 0.1 mg/g) and female (12.7 ± 0.7 mg/g) DMHCA-treated animals compared with control males (16.6 ± 2.8 mg/g) and females (13.2 ± 0.3 mg/g) (Table 2). Upon FPLC separation of plasma lipoproteins from fasted female animals, the TG content of the VLDL fraction was 55% decreased after DMHCA treatment (Fig. 6A), and the TC content was decreased by 29% (Fig. 6B).


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 distribution of triglycerides and cholesterol in plasma lipoprotein fractions of apoE-deficient mice. Lipoprotein profile of plasma pools of five fasted female apoE-deficient mice fed WTD ± DMHCA (8 mg/kg body weight/day) for 11 weeks. Plasma lipoproteins were separated by fast protein liquid chromatography. TG (A) and TC (B) concentrations in each fraction were measured enzymatically.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig6: Effect of DMHCA on distribution of triglycerides and cholesterol in plasma lipoprotein fractions of apoE-deficient mice. Lipoprotein profile of plasma pools of five fasted female apoE-deficient mice fed WTD ± DMHCA (8 mg/kg body weight/day) for 11 weeks. Plasma lipoproteins were separated by fast protein liquid chromatography. TG (A) and TC (B) concentrations in each fraction were measured enzymatically.
Mentions: Because we observed beneficial effects of DMHCA in wild-type mice, we further investigated the effect of DMHCA on body weight and lipid parameters in apoE-deficient mice during a long-term treatment. For that purpose, animals were fed WTD with or without DMHCA (8 mg/kg body weight/day) for 11 weeks. Although the food intake was similar in the different groups, male and female mice fed WTD plus DMHCA showed slightly decreased body weight gain when compared with mice fed WTD without DMHCA, which reached significance in female mice after 8 weeks of treatment (Fig. 5A, B). Plasma TC and TG levels were determined biweekly in the fed state. While no significant differences were observed in plasma TC (Fig. 5C) and TG (Fig. 5E) concentrations in male mice, female mice showed a significant decrease in TC (Fig. 5D) and TG (Fig. 5F) levels. Similar changes in plasma lipid levels were observed when mice were fasted overnight before blood was taken after 11 weeks of feeding WTD plus DMHCA (Table 2). We found reduced plasma TG levels in male (140 ± 10 mg/dl) and female (163 ± 9 mg/dl) apoE-deficient mice compared with mice fed WTD alone (197 ± 26 and 220 ± 5 mg/dl, respectively), whereas TC concentrations were significantly decreased only in male (799 ± 65 mg/dl vs. 1131 ± 52 mg/dl) but not in female animals (587 ± 33 mg/dl vs. 638 ± 16 mg/dl, respectively). No significant changes were found in HDL cholesterol levels. Determination of plasma AST or ALT levels did not give reliable results due to lipemic samples. Yet we determined bilirubin concentrations and found that they were comparable upon all diets. Therefore, long-time treatment did not lead to liver damage in apoE-deficient mice. Additionally, hepatic TG concentrations were unaltered in male (15.6 ± 0.1 mg/g) and female (12.7 ± 0.7 mg/g) DMHCA-treated animals compared with control males (16.6 ± 2.8 mg/g) and females (13.2 ± 0.3 mg/g) (Table 2). Upon FPLC separation of plasma lipoproteins from fasted female animals, the TG content of the VLDL fraction was 55% decreased after DMHCA treatment (Fig. 6A), and the TC content was decreased by 29% (Fig. 6B).

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