Obesity Decreases Hepatic 25-Hydroxylase Activity Causing Low Serum 25-Hydroxyvitamin D

Abstract

Normal vitamin D homeostasis is critical for optimal health; nevertheless, vitamin D deficiency is a worldwide public health problem. Vitamin D insufficiency is most commonly due to inadequate cutaneous synthesis of cholecalciferol and/or insufficient intake of vitamin D, but can also arise as a consequence of pathological states such as obesity. Serum concentrations of 25(OH)D (calcidiol) are low in obesity, and fail to increase appropriately after vitamin D supplementation. Although sequestration of vitamin D in adipose tissues or dilution of ingested or cutaneously synthesized vitamin D in the large fat mass of obese patients has been proposed to explain these findings, here we investigate the alternative mechanism that reduced capacity to convert parent vitamin D to 25(OH)D due to decreased expression of CYP2R1, the principal hepatic vitamin D 25-hydroxylase. To test this hypothesis, we isolated livers from female mice of 6 to 24 weeks of age, weaned onto either a normal chow diet or a high-fat diet, and determined the abundance of Cyp2r1 mRNA using digital droplet-quantitative PCR. We observed a significant (p < 0.001) decrease in Cyp2r1 mRNA in the liver of high-fat diet–fed mice relative to lean-chow–fed female mice. Moreover, there was a significant (p < 0.01) relationship between levels of Cyp2r1 mRNA and serum 25(OH)D concentrations as well as between Cyp2R1 mRNA and the ratio of circulating 25(OH)D3 to cholecalciferol (p < 0.0001). Using linear regression we determined a curve with 25(OH)D3/cholecalciferol versus normalized Cyp2R1 mRNA abundance with an R2 value of 0.85. Finally, we performed ex vivo activity assays of isolated livers and found that obese mice generated significantly less 25(OH)D3 than lean mice (p < 0.05). Our findings indicate that expression of CYP2R1 is reduced in obesity and accounts in part for the decreased circulating 25(OH)D.

Vitamin D Metabolism Revised: Fall of Dogmas

“…The causality (in whatever direction) between obesity/diabetes and low vitamin D status is, however, not proven. In a recent JBMR article, Roizen and colleagues clearly demonstrated that the serum concentration of 25OHD is substantially lower (~−20%) in serum of obese mice (fed a high‐fat diet) compared with normal‐weight mice, whereas serum concentrations of vitamin D 3 itself were similar in both groups . This is not a surprise because serum 25OHD concentrations in overweight or obese humans are virtually systematically lower than in normal subjects in many different areas of the world having different sun exposure or dietary habits .…”

“…PGC1α also induced hepatic and renal expression of CYP24A1 several‐fold, again mediated by the GR‐PGC1α‐ERRα pathway (but much less than the 100‐fold induction by 1,25(OH) 2 D). Other major fat‐regulating nuclear receptors are less likely involved, as the ENCODE project did not find consensus sequences for nuclear receptor (VDR) binding sites in promoters of genes involved in fat metabolism in the liver, such as constitutive androstane receptor (CAR), pregnane X receptor (PXR), or peroxisome proliferator‐activated receptor (PPAR) binding sites in the proximal promoter of mouse or human CYP2R1 (http://www.cbrc.jp/htbin/nph-tfsearch), but several binding sites for NFkB were identified …”

Response to: Obesity and Vitamin D Metabolism Modifications

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We thank Landrier and colleagues for their thoughtful comments regarding our recent publication regarding the role of decreased expression of CYP2R1 as a basis for reduced circulating levels of 25(OH)D in obese mice. (1) First, Landrier and colleagues point out one of the weaknesses that we ourselves had noted in our article, specifically that the cholecalciferol content of the two diets was not identical. They further assert that when diet composition is adjusted for vitamin D intake, obese mice show no differences from lean mice in serum 25(OH)D 3 concentrations.

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Obesity and Vitamin D Metabolism Modifications

“…Indeed, when the concentration of cholecalciferol is balanced between control and HF diets, to bring the same amounts of cholecalciferol to mice, taking into account the lowest consumption of HF diet, (8) the decrease of total 25(OH)D is not obvious. (2,3,9) In this context, it is surprising that in their study, Roizen et al (1) did not adjust the quantity of cholecalciferol between groups by increasing the cholecalciferol concentration in the HF diet. At the opposite, the concentration of cholecalciferol was reduced in the HF group (2.1 UI/g) compared with the control group (3.3 UI/g).…”

“…To the Editor, Roizen et al (1) published in the Journal of Bone and Mineral Research (JBMR) an interesting study related to the vitamin D metabolism in the context of obesity. Indeed, authors reported that a high fat (HF) diet resulted in modification of CYP2R1 expression (mRNA and protein), leading to a decrease of 25hydroxylase activity in the liver, which could explain the reduced serum 25-hydroxyvitamin D. Such observation is clearly in agreement with recent reports demonstrating that diet-induced obesity leads to modifications on the vitamin D metabolism, in the liver and in adipose tissue of mice, which may explain plasma vitamin D metabolites variations observed during obesity.…”