High‐methionine diets accelerate atherosclerosis by HHcy‐mediated FABP4 gene demethylation pathway via DNMT1 in ApoE<sup>−/−</sup> mice

Ai, Yang; Zhang, Huiping; Sun, Yue; Yang, Xia; Wang, Nan; Zhu, Gangjie; Zhang, Hui; Xu, Hui; Ma, Shengchao; Zhang, Yue; Li, Guizhong; Jia, Yanjie; Cao, Ji; Jiang, Yideng

doi:10.1016/j.febslet.2015.11.010

Cited by 62 publications

(71 citation statements)

References 39 publications

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“…In the present study, it was also found that B1 repetitive elements exhibited hypomethylation in the blood cells of the AS model. FABP4 has been identified as a potential circulation marker for metabolic syndrome, and is increased in individuals with diabetes and metabolic syndrome due to the development of subclinical inflammation, which leads to AS (44). The present study is the first, to the best of our knowledge to report that the methylation levels of FABP4 were closely associated with AS.…”

Section: Discussionsupporting

confidence: 49%

Ratio of S-adenosylmethionine to S-adenosylhomocysteine as a sensitive indicator of atherosclerosis

Zhang

Liu

et al. 2016

Mol Med Report

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Abstract. The present study aimed to confirm whether the ratio of S-adenosylmethionine (SAM) to S-adenosylhomocysteine (SAH) is a sensitive indicator, and whether it can be used as a biomarker for the clinical diagnosis of atherosclerosis. Apolipoprotein E (ApoE) -/-mice were randomly divided into four groups and fed with a high methionine diet for 15 weeks. Serum levels of homocysteine (Hcy) were measured using an automatic biochemistry analyzer. The concentrations of SAM and SAH were determined using high-performance liquid chromatography. The methylation levels of B1 repetitive elements, adipocyte fatty acid binding protein (FABP4), monocyte chemoattractant protein-1 (MCP-1) and extracellular superoxide dismutase (EC-SOD) were analyzed using nested touchdown-methylation-specific-polymerase chain reaction analysis. After 15 weeks, compared with the normal control group, serum concentrations of Hcy were significantly increased by 1.15-, 2.54-and 1.17-fold (P<0.05) in the ApoE -/-control group, Meth group and Meth-F group, respectively. The sizes of the atherosclerotic lesions were increased in the ApoE -/-control group, Meth group and Meth-F group, by up to 1.44-, 2.40-and 1.45-fold, respectively, compared with the normal control group (P<0.05). The concentrations of SAM were significantly increased by 3.02-, 3.42-and 2.46-fold in the ApoE -/-control group, Meth group and Meth-F group, respectively (P<0.05). The ratios of SAM/SAH were increased by 1.67-and 2.75-fold in the in ApoE -/-control group and Meth group, respectively, compared with the normal control group. The methylation levels of B1 repetitive elements, FABP4, MCP-1 and EC-SOD were decreased and exhibited hypomethylation. The methylation statuses of these genes were correlated with the ratio of the serum levels of SAM and SAH. These findings suggested that the SAM/SAH ratio is a biomarker and may provide a sensitive indicator for the clinical diagnosis of atherosclerosis.

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Section: Discussionsupporting

confidence: 49%

Ratio of S-adenosylmethionine to S-adenosylhomocysteine as a sensitive indicator of atherosclerosis

Zhang

Liu

et al. 2016

Mol Med Report

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“…Very recently, it has been reported that the ratio between SAM/SAH should be used as a biomarker and may provide a sensitive indicator for the clinical diagnosis of atherosclerosis [74]. Another scientific group investigate the effect of elevated Hcy level on fatty acid binding protein 4 (FABP4) [75]. Their results showed that FABP4 has a very important function in lipid metabolism disturbance after Hcy treatment and also that DNA methyltransferase 1 (DNMT1; EC 2.1.1.37) could be a potential therapeutic target in Hcy-related atherosclerosis [75].…”

Section: Hyperhomocysteinemia and Diseasesmentioning

confidence: 99%

“…Another scientific group investigate the effect of elevated Hcy level on fatty acid binding protein 4 (FABP4) [75]. Their results showed that FABP4 has a very important function in lipid metabolism disturbance after Hcy treatment and also that DNA methyltransferase 1 (DNMT1; EC 2.1.1.37) could be a potential therapeutic target in Hcy-related atherosclerosis [75]. …”

Section: Hyperhomocysteinemia and Diseasesmentioning

confidence: 99%

The Molecular and Cellular Effect of Homocysteine Metabolism Imbalance on Human Health

Škovierová

Vidomanová

Mahmood

et al. 2016

IJMS

346

238

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Homocysteine (Hcy) is a sulfur-containing non-proteinogenic amino acid derived in methionine metabolism. The increased level of Hcy in plasma, hyperhomocysteinemia, is considered to be an independent risk factor for cardio and cerebrovascular diseases. However, it is still not clear if Hcy is a marker or a causative agent of diseases. More and more research data suggest that Hcy is an important indicator for overall health status. This review represents the current understanding of molecular mechanism of Hcy metabolism and its link to hyperhomocysteinemia-related pathologies in humans. The aberrant Hcy metabolism could lead to the redox imbalance and oxidative stress resulting in elevated protein, nucleic acid and carbohydrate oxidation and lipoperoxidation, products known to be involved in cytotoxicity. Additionally, we examine the role of Hcy in thiolation of proteins, which results in their molecular and functional modifications. We also highlight the relationship between the imbalance in Hcy metabolism and pathogenesis of diseases, such as cardiovascular diseases, neurological and psychiatric disorders, chronic kidney disease, bone tissue damages, gastrointestinal disorders, cancer, and congenital defects.

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“…Previous reports have demonstrated that elevated levels of Hcy have been associated with a number of disease states, including AS (18,19). Despite the important contribution of Hcy to accelerated AS, the specific molecular mechanisms in response to Hcy within macrophages, which is important in atherogenesis, remain to be fully elucidated.…”

Section: Discussionmentioning

confidence: 99%

FABP4-mediated homocysteine-induced cholesterol accumulation in THP-1 monocyte-derived macrophages and the potential epigenetic mechanism

Jiang

Zhang

et al. 2016

Molecular Medicine Reports

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Abstract. Hyperhomocysteinemia (HHcy) is an independent risk factor for the development of atherosclerosis (AS), according to overwhelming number of clinical and epidemiological studies. However, the underlying pathogenic molecular mechanisms by which HHcy promotes AS remain to be fully elucidated. Fatty acid binding protein 4 (FABP4) has been shown to be important in macrophage cholesterol trafficking. The objective of the present study was to determine whether homocysteine (Hcy) accelerates AS through regulating FABP4, and then mediates cholesterol accumulation in macrophages. Hcy concentrations of 0, 50, 100, 200 and 500 µM, and 100 µM Hcy+30 µM vitamin B 12 (VB 12 )+30 µM folic acid (FA) were respectively added to cultured THP-1 monocyte-derived macrophages for 24 h. The levels of FABP4, which acts as a key factor connecting cellular lipid accumulation to inflammation, were determined using reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blot analyses in the macrophages. The present study used a nested touchdown methylation-specific PCR assay to detect the DNA methylation status of the FABP4 promoter region. In addition, the FABP4 gene fragment was inserted into the cloning vector, pcDNA3.1-EGFP, to construct the recombinant plasmid, pcDNA3.1-EGFP/FABP4, which was identified using restriction endonuclease digestion analysis and DNA sequencing. The pcDNA3.1-EGFP/FABP4 expression plasmid was transfected into THP-1 monocyte-derived macrophages, mediated by liposome reagent, following which the expression levels of FABP4 were detected using RT-qPCR and western blot analyses. The present study also determined the intracellular accumulation of total cholesterol in the macrophages. The results indicated that Hcy decreased the levels of FABP4 promoter methylation, but increased the mRNA and protein expression levels of FABP4 in the macrophages, compared with the control group (0 µM Hcy). However, no dose-dependent changes were observed with increasing concentrations of Hcy. The recombinant fluorescent eukaryotic expression vector, pcDNA3.1-EGFP/FABP4, was successfully constructed and effectively expressed in the THP-1 macrophages. The results also showed that FABP4 accelerated the accumulation of cholesterol in the macrophages. Taken together, the results of the present study suggested that FABP4 DNA hypomethylation induced by Hcy may be involved in the overexpression of FABP4, thereby inducing cholesterol accumulation in macrophages.

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High‐methionine diets accelerate atherosclerosis by HHcy‐mediated FABP4 gene demethylation pathway via DNMT1 in ApoE^−/− mice

Cited by 62 publications

References 39 publications

Ratio of S-adenosylmethionine to S-adenosylhomocysteine as a sensitive indicator of atherosclerosis

Ratio of S-adenosylmethionine to S-adenosylhomocysteine as a sensitive indicator of atherosclerosis

The Molecular and Cellular Effect of Homocysteine Metabolism Imbalance on Human Health

FABP4-mediated homocysteine-induced cholesterol accumulation in THP-1 monocyte-derived macrophages and the potential epigenetic mechanism

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High‐methionine diets accelerate atherosclerosis by HHcy‐mediated FABP4 gene demethylation pathway via DNMT1 in ApoE−/− mice

Cited by 62 publications

References 39 publications

Ratio of S-adenosylmethionine to S-adenosylhomocysteine as a sensitive indicator of atherosclerosis

Ratio of S-adenosylmethionine to S-adenosylhomocysteine as a sensitive indicator of atherosclerosis

The Molecular and Cellular Effect of Homocysteine Metabolism Imbalance on Human Health

FABP4-mediated homocysteine-induced cholesterol accumulation in THP-1 monocyte-derived macrophages and the potential epigenetic mechanism

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High‐methionine diets accelerate atherosclerosis by HHcy‐mediated FABP4 gene demethylation pathway via DNMT1 in ApoE^−/− mice