Low Vitamin B12 and Lipid Metabolism: Evidence from Pre-Clinical and Clinical Studies

Abstract

Obesity is a worldwide epidemic responsible for 5% of global mortality. The risks of developing other key metabolic disorders like diabetes, hypertension and cardiovascular diseases (CVDs) are increased by obesity, causing a great public health concern. A series of epidemiological studies and animal models have demonstrated a relationship between the importance of vitamin B12 (B12) and various components of metabolic syndrome. High prevalence of low B12 levels has been shown in European (27%) and South Indian (32%) patients with type 2 diabetes (T2D). A longitudinal prospective study in pregnant women has shown that low B12 status could independently predict the development of T2D five years after delivery. Likewise, children born to mothers with low B12 levels may have excess fat accumulation which in turn can result in higher insulin resistance and risk of T2D and/or CVD in adulthood. However, the independent role of B12 on lipid metabolism, a key risk factor for cardiometabolic disorders, has not been explored to a larger extent. In this review, we provide evidence from pre-clinical and clinical studies on the role of low B12 status on lipid metabolism and insights on the possible epigenetic mechanisms including DNA methylation, micro-RNA and histone modifications. Although, there are only a few association studies of B12 on epigenetic mechanisms, novel approaches to understand the functional changes caused by these epigenetic markers are warranted.

Keywords: cardiovascular disease (CVD); lipid metabolism; metabolic syndrome (MetS); obesity; type 2 diabetes mellitus (T2D); vitamin B12 (B12).

Figure 1

Cellular (hepatocyte) uptake and metabolism of vitamin B12 (B12): Cells generally internalize B12-bound transcobolamin (holo-TC) with the aid of transcobalamin receptor (TCR) TCbIR/CD320 via endocytosis and fused into lysosomes. Within this organelle, B12 is liberated from the TC with the latter (Apo-TC) subjected to degradation whilst the former (B12) is transported to the cytosol and further processed to its catalytic forms, methyl-cobalamin (MeCbl) and 5′-adenosyl cobalamin (AdoCbl), acting in the cytosol and mitochondria as co-enzymes in the methyl malonyl CoA mutase (MCM) and methionine synthase (MS) pathways, respectively. The transcobalamin receptors (TCbIR) are however recycled back to the cellular surface membrane.

Figure 2

Cellular role of B12 in lipogenesis. There is a reduction in the production of methionine as well as the methyl donor s-adenosyl methionine (SAM) within the cell’s cytosol, resulting from B12 deficiency, leading to hyperhomocysteinemia as well as reversible increase in s-adenosyl homocysteine (SAH) which is known to be an inhibitor of DNA methyl transferases (DNMTs). The inhibition of DNMTs together with low levels of SAM results in hypomethylation of DNA and altered gene expressions. Beta oxidation of fatty acid is inhibited by generation of methyl malonic acid (MMA) from methyl malonyl-CoA within the mitochondria due to insufficiency of B12, a cofactor for methyl malonyl-CoA mutase (MCM) enzyme required for the biosynthesis of succinyl-CoA from methyl malonyl-CoA in the propionate metabolism pathway.