Vitamin B12 insufficiency induces cholesterol biosynthesis by limiting s-adenosylmethionine and modulating the methylation of SREBF1 and LDLR genes.
Vitamin B12 insufficiency induces cholesterol biosynthesis by limiting s-adenosylmethionine and modulating the methylation of SREBF1 and LDLR genes.
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DOI：
10.1186/s13148-015-0046-8
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发表时间：
2015
影响因子：
5.7
通讯作者：
Tripathi G
中科院分区：
文献类型：
--
作者：
Adaikalakoteswari A;Finer S;Voyias PD;McCarthy CM;Vatish M;Moore J;Smart-Halajko M;Bawazeer N;Al-Daghri NM;McTernan PG;Kumar S;Hitman GA;Saravanan P;Tripathi G
膳食中提供的甲基供体如叶酸、维生素B12、甜菜碱、蛋氨酸和胆碱对整个生命过程中的正常生长、发育和生理功能至关重要。人类和动物研究都表明，维生素B12缺乏与血脂谱改变有关，并在预测代谢风险方面发挥重要作用，然而，迄今为止，还没有研究证实这一点的直接机制。三个独立的临床研究的妇女（i）非怀孕的育龄期，（ii）在怀孕早期，（iii）在交付表明，低维生素B12状态与较高的总胆固醇，低密度脂蛋白胆固醇，胆固醇与高密度脂蛋白的比例。这些结果指导了以人脂肪细胞为模型系统，对维生素B12缺乏引起的胆固醇生物合成的细胞机制的研究。与对照组相比，在低维生素B12或无维生素B12条件下培养的脂肪细胞胆固醇和同型半胱氨酸水平升高。胆固醇生物合成的诱导与降低的S-腺苷甲硫氨酸（NAMet）与S-腺苷高半胱氨酸（NAHcy）比率（也称为甲基化潜力（MP））相关。因此，我们研究是否减少MP可能导致参与胆固醇生物合成调控的基因的低甲基化。全基因组和靶向DNA甲基化分析发现，SREBF 1和LDLR的启动子区域，胆固醇生物合成的两个关键调节因子，在维生素B12缺乏条件下低甲基化，因此，它们的表达和胆固醇生物合成也显着增加。通过添加甲基化抑制剂5-氮杂-2 ′-脱氧胞苷进一步证实了这一发现，这导致在维生素B12充足的条件下SREBF 1和LDLR表达增加以及胆固醇蓄积。最后，我们观察到，与对照组相比，维生素B12缺乏母亲的脂肪组织中SREBF 1，LDLR和胆固醇生物合成基因的表达增加。临床数据表明，维生素B12缺乏是一个重要的代谢危险因素。维生素B12对人脂肪细胞胆固醇生物合成途径的影响可能是其调控人脂肪细胞胆固醇合成途径的重要机制。本文的在线版本（doi：10.1186/s13148-015-0046-8）包含补充材料，可供授权用户使用。
The dietary supply of methyl donors such as folate, vitamin B12, betaine, methionine, and choline is essential for normal growth, development, and physiological functions through the life course. Both human and animal studies have shown that vitamin B12 deficiency is associated with altered lipid profile and play an important role in the prediction of metabolic risk, however, as of yet, no direct mechanism has been investigated to confirm this. Three independent clinical studies of women (i) non-pregnant at child-bearing age, (ii) in early pregnancy, and (iii) at delivery showed that low vitamin B12 status was associated with higher total cholesterol, LDL cholesterol, and cholesterol-to-HDL ratio. These results guided the investigation into the cellular mechanisms of induced cholesterol biosynthesis due to vitamin B12 deficiency, using human adipocytes as a model system. Adipocytes cultured in low or no vitamin B12 conditions had increased cholesterol and homocysteine levels compared to control. The induction of cholesterol biosynthesis was associated with reduced s-adenosylmethionine (AdoMet)-to-s-adenosylhomocysteine (AdoHcy) ratio, also known as methylation potential (MP). We therefore studied whether reduced MP could lead to hypomethylation of genes involved in the regulation of cholesterol biosynthesis. Genome-wide and targeted DNA methylation analysis identified that the promoter regions of SREBF1 and LDLR, two key regulators of cholesterol biosynthesis, were hypomethylated under vitamin B12-deficient conditions, and as a result, their expressions and cholesterol biosynthesis were also significantly increased. This finding was further confirmed by the addition of the methylation inhibitor, 5-aza-2′-deoxycytidine, which resulted in increased SREBF1 and LDLR expressions and cholesterol accumulation in vitamin B12-sufficient conditions. Finally, we observed that the expression of SREBF1, LDLR, and cholesterol biosynthesis genes were increased in adipose tissue of vitamin B12 deficient mothers compared to control group. Clinical data suggests that vitamin B12 deficiency is an important metabolic risk factor. Regulation of AdoMet-to-AdoHcy levels by vitamin B12 could be an important mechanism by which it can influence cholesterol biosynthesis pathway in human adipocytes. The online version of this article (doi:10.1186/s13148-015-0046-8) contains supplementary material, which is available to authorized users.
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影响因子：
4.5
作者：
Fernàndez-Roig S;Lai SC;Murphy MM;Fernandez-Ballart J;Quadros EV
通讯作者：
Quadros EV
影响因子：
15.9
作者：
Chui, PC;Guan, HP;Lazar, MA
通讯作者：
Lazar, MA
影响因子：
3.3
作者：
Mesmin B;Pipalia NH;Lund FW;Ramlall TF;Sokolov A;Eliezer D;Maxfield FR
通讯作者：
Maxfield FR
影响因子：
8.2
作者：
Krishnaveni, G. V.;Hill, J. C.;Veena, S. R.;Bhat, D. S.;Wills, A. K.;Karat, C. L. S.;Yajnik, C. S.;Fall, C. H. D.
通讯作者：
Fall, C. H. D.
DOI：
10.1073/pnas.1534923100
发表时间：
2003-10-14
影响因子：
11.1
作者：
Horton, JD;Shah, NA;Goldstein, JL
通讯作者：
Goldstein, JL