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Impact of chronic low to moderate alcohol consumption on blood lipid and heart energy profile in acetaldehyde dehydrogenase 2-deficient mice.

Fan F, Cao Q, Wang C, Ma X, Shen C, Liu XW, Bu LP, Zou YZ, Hu K, Sun AJ, Ge JB - Acta Pharmacol. Sin. (2014)

Bottom Line: Serum ethanol and acetaldehyde levels and blood lipids were measured.Metabolomics was used to characterize the heart and serum metabolism profiles.Thus, preserved ALDH2 function is essential for the protective effect of low to moderate alcohol on the cardiovascular system.

View Article: PubMed Central - PubMed

Affiliation: Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai 200032, China.

ABSTRACT

Aim: To investigate the roles of acetaldehyde dehydrogenase 2 (ALDH2), the key enzyme of ethanol metabolism, in chronic low to moderate alcohol consumption-induced heart protective effects in mice.

Methods: Twenty-one male wild-type (WT) or ALDH2-knockout (KO) mice were used in this study. In each genotype, 14 animals received alcohol (2.5%, 5% and 10% in week 1-3, respectively, and 18% in week 4-7), and 7 received water for 7 weeks. After the treatments, survival rate and general characteristics of the animals were evaluated. Serum ethanol and acetaldehyde levels and blood lipids were measured. Metabolomics was used to characterize the heart and serum metabolism profiles.

Results: Chronic alcohol intake decreased the survival rate of KO mice by 50%, and significantly decreased their body weight, but did not affect those of WT mice. Chronic alcohol intake significantly increased the serum ethanol levels in both WT and KO mice, but KO mice had significantly higher serum acetaldehyde levels than WT mice. Chronic alcohol intake significantly increased the serum HDL cholesterol levels in WT mice, and did not change the serum HDL cholesterol levels in KO mice. After chronic alcohol intake, WT and KO mice showed differential heart and serum metabolism profiles, including the 3 main energy substrate types (lipids, glucose and amino acids) and three carboxylic acid cycles.

Conclusion: Low to moderate alcohol consumption increases HDL cholesterol levels and improves heart energy metabolism profile in WT mice but not in ALDH2-KO mice. Thus, preserved ALDH2 function is essential for the protective effect of low to moderate alcohol on the cardiovascular system.

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Effect of ALDH2 deficiency on the heart and serum metabolism profiles post-alcohol consumption. (A, C) PCA score plot of cardiac and serum metabolite profiles after metabolomics analysis. (B, D) Heatmaps of differentially expressed metabolites, which were classified according to pathway. Red indicates up-regulation, and green indicates down-regulation.
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fig4: Effect of ALDH2 deficiency on the heart and serum metabolism profiles post-alcohol consumption. (A, C) PCA score plot of cardiac and serum metabolite profiles after metabolomics analysis. (B, D) Heatmaps of differentially expressed metabolites, which were classified according to pathway. Red indicates up-regulation, and green indicates down-regulation.

Mentions: The variations in the cardiac and serum lipid metabolite profiles and in the carbohydrate, amino acid and three carboxylic acid cycle metabolite profiles were measured by metabolomics. Approximately 300 metabolites were identified and quantified by the high-performance liquid chromatography time-of-flight mass spectrometry (HPLC-TOF-MS) method. Principal component analysis (PCA) was performed (Figure 4A, 4C) on both heart and serum data to observe the similarities or differences among the four groups. The PCA score plot for the heart tissue (Figure 4A) showed that the four groups were well separated. In particular, the WT ethanol and KO ethanol groups were separated by the first principal component. These data indicated that the differences in the metabolic parameters are mainly caused by the ALDH2 deficiency. The serum samples were not separated as well as the heart tissue samples. Then a heatmap was generated for metabolites with significant differences between at least two groups (Figure 4B, 4C), and those metabolites were separated into different metabolic pathways. Significant metabolites were selected based on the VIP value (VIP>1) from a typical 7-fold cross-validated orthogonal partial least squares discriminant analysis (OPLS-DA) model and the P-value (P<0.05) of t-test statistics. Differences were found in 23 lipid metabolites from heart tissue and 33 from serum, in 14 carbohydrates from heart and 4 from serum, in 15 amino acids from heart and 8 from serum, and in 8 three-carboxylic acid cycle members from heart and 4 from serum. These data suggest that the metabolite profiles reflect the different metabolic patterns. A detailed list of the differential heart metabolites (WT vs WT±alcohol, KO vs KO±alcohol, WT±alcohol vs KO±alcohol) are shown in Table S1. The differential serum metabolites are shown in Table S2. Both the heart and serum results show that after chronic low to moderate alcohol consumption, lipid metabolites such as stearic acid, oleic acid, and various phospholipids were decreased, and glucose metabolites such as α-D-glucose-6-phosphate, Shikimate-3-phosphate and gluconic acid were increased in ALDH2 KO mice compared with WT mice. These data indicate that ALDH2 deficiency may regulate the lipid-glucose metabolism balance after alcohol consumption. Sketch maps of lipids, glucose and citrate cycle (TCA cycle) members derived from bioinformatic analysis according to the KEGG database are shown in Figure S2.


Impact of chronic low to moderate alcohol consumption on blood lipid and heart energy profile in acetaldehyde dehydrogenase 2-deficient mice.

Fan F, Cao Q, Wang C, Ma X, Shen C, Liu XW, Bu LP, Zou YZ, Hu K, Sun AJ, Ge JB - Acta Pharmacol. Sin. (2014)

Effect of ALDH2 deficiency on the heart and serum metabolism profiles post-alcohol consumption. (A, C) PCA score plot of cardiac and serum metabolite profiles after metabolomics analysis. (B, D) Heatmaps of differentially expressed metabolites, which were classified according to pathway. Red indicates up-regulation, and green indicates down-regulation.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4125715&req=5

fig4: Effect of ALDH2 deficiency on the heart and serum metabolism profiles post-alcohol consumption. (A, C) PCA score plot of cardiac and serum metabolite profiles after metabolomics analysis. (B, D) Heatmaps of differentially expressed metabolites, which were classified according to pathway. Red indicates up-regulation, and green indicates down-regulation.
Mentions: The variations in the cardiac and serum lipid metabolite profiles and in the carbohydrate, amino acid and three carboxylic acid cycle metabolite profiles were measured by metabolomics. Approximately 300 metabolites were identified and quantified by the high-performance liquid chromatography time-of-flight mass spectrometry (HPLC-TOF-MS) method. Principal component analysis (PCA) was performed (Figure 4A, 4C) on both heart and serum data to observe the similarities or differences among the four groups. The PCA score plot for the heart tissue (Figure 4A) showed that the four groups were well separated. In particular, the WT ethanol and KO ethanol groups were separated by the first principal component. These data indicated that the differences in the metabolic parameters are mainly caused by the ALDH2 deficiency. The serum samples were not separated as well as the heart tissue samples. Then a heatmap was generated for metabolites with significant differences between at least two groups (Figure 4B, 4C), and those metabolites were separated into different metabolic pathways. Significant metabolites were selected based on the VIP value (VIP>1) from a typical 7-fold cross-validated orthogonal partial least squares discriminant analysis (OPLS-DA) model and the P-value (P<0.05) of t-test statistics. Differences were found in 23 lipid metabolites from heart tissue and 33 from serum, in 14 carbohydrates from heart and 4 from serum, in 15 amino acids from heart and 8 from serum, and in 8 three-carboxylic acid cycle members from heart and 4 from serum. These data suggest that the metabolite profiles reflect the different metabolic patterns. A detailed list of the differential heart metabolites (WT vs WT±alcohol, KO vs KO±alcohol, WT±alcohol vs KO±alcohol) are shown in Table S1. The differential serum metabolites are shown in Table S2. Both the heart and serum results show that after chronic low to moderate alcohol consumption, lipid metabolites such as stearic acid, oleic acid, and various phospholipids were decreased, and glucose metabolites such as α-D-glucose-6-phosphate, Shikimate-3-phosphate and gluconic acid were increased in ALDH2 KO mice compared with WT mice. These data indicate that ALDH2 deficiency may regulate the lipid-glucose metabolism balance after alcohol consumption. Sketch maps of lipids, glucose and citrate cycle (TCA cycle) members derived from bioinformatic analysis according to the KEGG database are shown in Figure S2.

Bottom Line: Serum ethanol and acetaldehyde levels and blood lipids were measured.Metabolomics was used to characterize the heart and serum metabolism profiles.Thus, preserved ALDH2 function is essential for the protective effect of low to moderate alcohol on the cardiovascular system.

View Article: PubMed Central - PubMed

Affiliation: Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai 200032, China.

ABSTRACT

Aim: To investigate the roles of acetaldehyde dehydrogenase 2 (ALDH2), the key enzyme of ethanol metabolism, in chronic low to moderate alcohol consumption-induced heart protective effects in mice.

Methods: Twenty-one male wild-type (WT) or ALDH2-knockout (KO) mice were used in this study. In each genotype, 14 animals received alcohol (2.5%, 5% and 10% in week 1-3, respectively, and 18% in week 4-7), and 7 received water for 7 weeks. After the treatments, survival rate and general characteristics of the animals were evaluated. Serum ethanol and acetaldehyde levels and blood lipids were measured. Metabolomics was used to characterize the heart and serum metabolism profiles.

Results: Chronic alcohol intake decreased the survival rate of KO mice by 50%, and significantly decreased their body weight, but did not affect those of WT mice. Chronic alcohol intake significantly increased the serum ethanol levels in both WT and KO mice, but KO mice had significantly higher serum acetaldehyde levels than WT mice. Chronic alcohol intake significantly increased the serum HDL cholesterol levels in WT mice, and did not change the serum HDL cholesterol levels in KO mice. After chronic alcohol intake, WT and KO mice showed differential heart and serum metabolism profiles, including the 3 main energy substrate types (lipids, glucose and amino acids) and three carboxylic acid cycles.

Conclusion: Low to moderate alcohol consumption increases HDL cholesterol levels and improves heart energy metabolism profile in WT mice but not in ALDH2-KO mice. Thus, preserved ALDH2 function is essential for the protective effect of low to moderate alcohol on the cardiovascular system.

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