Vitamin B12 deficiency induces cholesterol biosynthesis by limiting S-adenosyl methionine and altering the methylation of Srebf1 and Ldlr genes
AffiliationUniversity of Westminster
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AbstractMaternal vitamin B12 deficiency affecting one-carbonmetabolism influences metabolic status and the degree of insulinresistance of the offspring in adulthood. But its significance andmechanism in the development of adiposity and adipose tissuedysfunction is unknown. To investigate the role of vitamin B12 in the developmentof adipocyte dysfunction. Human pre-adipocytes were differentiatedin customised media with varying concentrations of B12. Adipo-cytes cultured in low B12 (0.15nM) or no B12 conditions hadincreased cholesterol and homocysteine levels and reduced glucoseuptake capacity compared to control (B12 500nM). Global DNAmethylation profiling and bisulphite pyrosequencing showed thatthe promoter regions of sterol regulatory element-binding tran-scription factor 1 (SREBF1) and low density lipoprotein receptor(LDLR) were hypomethylated in B12 deficient conditions, consis-tent with the increased gene expressions. The S-adenosyl methio-nine/S-adenosyl homocysteine ratio was significantly lower in B12deficient conditions. Inhibition of methylation in high B12 condi-tions by 5-aza-2-deoxycytidine led to increased cholesterol accu-mulation but not homocysteine. In two independent clinicalstudies, women at child bearing age (age: 19–39 years) and inearly pregnancy (16–18 weeks), showed that low B12 was asso-ciated with higher total cholesterol, LDL cholesterol and choles-terol to HDL ratio. Regression analysis in the pregnant cohortadjusting for all confounders showed B12 levels to be indepen-dently associated with total cholesterol and triglyceride levels. Vitamin B12 deficiency leads to adipocyte dysfunc-tion by inducing cholesterol biosynthesis and homocysteine.Induction of cholesterol biosynthesis was due to hypomethylationof SREBF1 and LDLR. Clinical observations support that the B12effect is independent and our findings show this link is probably causal.
CitationAdaikalakoteswari, A., Finer, S., Voyias, P.D., McCarthy, C., Moore, J., Smart-Halajko, M., Bawazeer, N., Al-Daghri, N.M. and McTernan, P.G., (2015). 'Vitamin B12 deficiency induces cholesterol biosynthesis by limiting S-adenosyl methionine and altering the methylation of SREBF1 and LDLR genes'. Poster exhibited at the Diabetes UK Professional Conference, London, 11-13 March.