Vitamin B12 insufficiency induces cholesterol biosynthesis by limiting s-adenosylmethionine and modulating the methylation of SREBF1 and LDLR genes

Abstract

BackgroundThe 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.ResultsThree 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.ConclusionsClinical 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s13148-015-0046-8) contains supplementary material, which is available to authorized users.

Prevalence of vitamin B-12 insufficiency during pregnancy and its effect on offspring birth weight: a systematic review and meta-analysis

“…The "Mediterranean diet" contains plenty of fruit, vegetables, and pulses compared with meat (118), which may in part explain this observation because stricter adherence to the diet during pregnancy exacerbated vitamin B-12 deficiency (52). In addition, obesity rates are high in these regions (119), and obesity has been shown to be associated with low vitamin B-12 (79,(120)(121)(122). The link between obesity, gestational diabetes, and low vitamin B-12 concentrations has not been fully explored, but because the former 2 conditions are independently associated with fetal macrosomia, they may partly compensate for or mask the associations between vitamin B-12 and LBW (123,124).…”

Vitamin B12 Status among Pregnant Women in the UK and Its Association with Obesity and Gestational Diabetes

“…Additionally, the mitochondrial conversion of methylmalonyl-CoA to succinyl-CoA requires B12 as a coenzyme and in its absence, accumulation of the former compound inhibits fatty acid oxidation, thereby promoting lipogenesis [7,8]. Therefore it can be postulated that low B12, at a cellular level, may be linked to adipocyte dysfunction and obesity-related complications by modulating lipid metabolism, cellular inflammation [9], and causing hypomethylation of cholesterol biosynthesis pathways [10]. …”

“…Low B12 during pregnancy has implications for materno-fetal health including maternal adiposity, maternal and offspring insulin resistance [12,13,14], and adverse lipid profile in neonates [10,15]. The first two observations were replicated in a cohort of women without GDM from South West England [16] but there are no data available on the role of B12 in GDM in the UK.…”

Guide for Current Nutrigenetic, Nutrigenomic, and Nutriepigenetic Approaches for Precision Nutrition Involving the Prevention and Management of Chronic Diseases Associated with Obesity

“…Also, choline- and folate-deficient diets were associated with dysregulation of genes involved in lipid metabolism, thus influencing the susceptibility and severity of NAFLD [48]. Chromium deficiency downregulated insulin signaling genes, thus demonstrating a role in T2DM pathogenesis [49], whereas deprivations of selenium [50], vitamin B 12 [51], and vitamin A [52], could increase CVD susceptibility by upregulating proinflammatory and lipogenic genes.…”