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Vitamin B12 insufficiency induces cholesterol biosynthesis by limiting s-adenosylmethionine and modulating the methylation of SREBF1 and LDLR genes
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Adaikalakoteswari, Antonysunil, Finer, Sarah, Voyias, Philip D., McCarthy, Ciara M., Vatish, Manu, Moore, Jonathan D., Smart-Halajko, Melissa, Bawazeer, Nahla M., Al-Daghri, Nasser M., McTernan, P. G., Kumar, Sudhesh, Hitman, Graham A., Saravanan, Ponnusamy and Tripathi, Gyanendra (2015) Vitamin B12 insufficiency induces cholesterol biosynthesis by limiting s-adenosylmethionine and modulating the methylation of SREBF1 and LDLR genes. Clinical Epigenetics, Volume 7 (Number 1). pp. 1-14. Article number 14. doi:10.1186/s13148-015-0046-8 ISSN 1868-7075.
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Official URL: http://dx.doi.org/10.1186/s13148-015-0046-8
Abstract
Background:
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.
Results:
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.
Conclusions:
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.
Item Type: | Journal Article | ||||||||
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Subjects: | Q Science > QP Physiology | ||||||||
Divisions: | Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School > Dean's Office & Professional Support Services Faculty of Science, Engineering and Medicine > Research Centres > Warwick Systems Biology Centre Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School |
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Library of Congress Subject Headings (LCSH): | Vitamin B12, Folic acid, Cholesterol, Homocysteine, Fat cells, Methylation, Child development | ||||||||
Journal or Publication Title: | Clinical Epigenetics | ||||||||
Publisher: | BioMed Central Ltd. | ||||||||
ISSN: | 1868-7075 | ||||||||
Official Date: | 27 February 2015 | ||||||||
Dates: |
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Volume: | Volume 7 | ||||||||
Number: | Number 1 | ||||||||
Number of Pages: | 14 | ||||||||
Page Range: | pp. 1-14 | ||||||||
Article Number: | Article number 14 | ||||||||
DOI: | 10.1186/s13148-015-0046-8 | ||||||||
Status: | Peer Reviewed | ||||||||
Publication Status: | Published | ||||||||
Access rights to Published version: | Open Access (Creative Commons) | ||||||||
Date of first compliant deposit: | 29 December 2015 | ||||||||
Date of first compliant Open Access: | 29 December 2015 | ||||||||
Funder: | King Saud University, Riyadh, (KSA), Research Councils UK (RCUK), Advantage West Midlands (AWM) |
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