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Vitamin K in Human Health and Disease

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A special issue of Nutrients (ISSN 2072-6643).

Deadline for manuscript submissions: closed (31 July 2018) | Viewed by 69610

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Prof. Dr. Guylaine Ferland

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Guest Editor

Research Centre, Montreal Heart Institute, Université de Montréal, Montreal, QC H1T 1C8, Canada
Interests: nutrition; vitamin K metabolism; ageing; brain function; Alzheimer’s disease; cardiovascular disease; nutrition interventions; nutrition requirements

Dr. Mathieu Ferron

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Guest Editor

Institut de Recherches Cliniques de Montréal, Université de Montréal & Research Unit, Montreal, PQ H2W 1R7, Canada
Interests: vitamin K; vitamin K reductases; protein gamma-carboxylation; bone metabolism; glucose metabolism; insulin secretion; insulin sensitivity

Special Issue Information

Dear Colleagues,

Initially discovered for its role in blood coagulation, it is now recognized that vitamin K (VK) is involved in many physiological systems besides hemostasis. Furthermore, it is now emerging that VK has biological and clinical roles that extend beyond its well-characterized action as an enzyme cofactor for the carboxylation of the VK-dependent proteins (VKDP). The aim of this Special Issue, entitled “Vitamin K in Human Health and Disease”, is to share the latest research findings on topics, such as (but not exclusively) the molecular aspects of VK cycle and metabolism (i.e., VKORC1, VKORC1L1), the VKDP as regards their emerging roles in energy metabolism and endocrine function (i.e., osteocalcin), the calcification process (i.e., matrix Gla protein) and brain function (i.e., Gas6), and the non-enzymatic role of menaquinone-4 (MK-4). These basic aspects of VK functions and metabolism will be discussed in the context of various chronic diseases, i.e., diabetes, CVD, CKD, cognitive impairment, and considering the modulatory role of VK nutritional status.

Prof. Dr. Guylaine Ferland
Dr. Mathieu Ferron
Guest Editors

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Keywords

Vitamin K (VK)
Menaquinone-4 (MK-4)
VKOR (VKORC1, VKORC1L1)
Vitamin K-dependent proteins (VKDP)
Matrix Gla protein
Osteocalcin
Calcification process
Endocrine function
Energy metabolism
Diabetes
Cardiovascular disease (CVD)
Chronic kidney disease (CKD)
Brain function

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Published Papers (10 papers)

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Research

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12 pages, 1032 KiB

Open AccessArticle

A Novel Biomimetic Tool for Assessing Vitamin K Status Based on Molecularly Imprinted Polymers

by Kasper Eersels, Hanne Diliën, Joseph W. Lowdon, Erik Steen Redeker, Renato Rogosic, Benjamin Heidt, Marloes Peeters, Peter Cornelis, Petra Lux, Chris P. Reutelingsperger, Leon J. Schurgers, Thomas J. Cleij and Bart Van Grinsven

Nutrients 2018, 10(6), 751; https://doi.org/10.3390/nu10060751 - 11 Jun 2018

Cited by 14 | Viewed by 5852

Abstract

Vitamin K was originally discovered as a cofactor required to activate clotting factors and has recently been shown to play a key role in the regulation of soft tissue calcification. This property of vitamin K has led to an increased interest in novel methods for accurate vitamin K detection. Molecularly Imprinted Polymers (MIPs) could offer a solution, as they have been used as synthetic receptors in a large variety of biomimetic sensors for the detection of similar molecules over the past few decades, because of their robust nature and remarkable selectivity. In this article, the authors introduce a novel imprinting approach to create a MIP that is able to selectively rebind vitamin K₁. As the native structure of the vitamin does not allow for imprinting, an alternative imprinting strategy was developed, using the synthetic compound menadione (vitamin K₃) as a template. Target rebinding was analyzed by means of UV-visible (UV-VIS) spectroscopy and two custom-made thermal readout techniques. This analysis reveals that the MIP-based sensor reacts to an increasing concentration of both menadione and vitamin K₁. The Limit of Detection (LoD) for both compounds was established at 700 nM for the Heat Transfer Method (HTM), while the optimized readout approach, Thermal Wave Transport Analysis (TWTA), displayed an increased sensitivity with a LoD of 200 nM. The sensor seems to react to a lesser extent to Vitamin E, the analogue under study. To further demonstrate its potential application in biochemical research, the sensor was used to measure the absorption of vitamin K in blood serum after taking vitamin K supplements. By employing a gradual enrichment strategy, the sensor was able to detect the difference between baseline and peak absorption samples and was able to quantify the vitamin K concentration in good agreement with a validation experiment using High-Performance Liquid Chromatography (HPLC). In this way, the authors provide a first proof of principle for a low-cost, straightforward, and label-free vitamin K sensor. Full article

(This article belongs to the Special Issue Vitamin K in Human Health and Disease)

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7 pages, 396 KiB

Open AccessArticle

Decreased Levels of Circulating Carboxylated Osteocalcin in Children with Low Energy Fractures: A Pilot Study

by Janusz Popko, Michał Karpiński, Sylwia Chojnowska, Katarzyna Maresz, Robert Milewski, Vladimir Badmaev and Leon J. Schurgers

Nutrients 2018, 10(6), 734; https://doi.org/10.3390/nu10060734 - 6 Jun 2018

Cited by 12 | Viewed by 7323

Abstract

Objective: In the past decades, an increased interest in the roles of vitamin D and K has become evident, in particular in relation to bone health and prevention of bone fractures. The aim of the current study was to evaluate vitamin D and K status in children with low-energy fractures and in children without fractures. Methods: The study group of 20 children (14 boys, 6 girls) aged 5 to 15 years old, with radiologically confirmed low-energy fractures was compared with the control group of 19 healthy children (9 boys, 10 girls), aged 7 to 17 years old, without fractures. Total vitamin D (25(OH)D3 plus 25(OH)D2), calcium, BALP (bone alkaline phosphatase), NTx (N-terminal telopeptide), and uncarboxylated (ucOC) and carboxylated osteocalcin (cOC) serum concentrations were evaluated. Ratio of serum uncarboxylated osteocalcin to serum carboxylated osteocalcin ucOC:cOC (UCR) was used as an indicator of bone vitamin K status. Logistic regression models were created to establish UCR influence for odds ratio of low-energy fractures in both groups. Results: There were no statistically significant differences in the serum calcium, NTx, BALP, or total vitamin D levels between the two groups. There was, however, a statistically significant difference in the UCR ratio. The median UCR in the fracture group was 0.471 compared with the control group value of 0.245 (p < 0.0001). In the logistic regression analysis, odds ratio of low-energy fractures for UCR was calculated, with an increased risk of fractures by some 78.3 times. Conclusions: In this pilot study, better vitamin K status expressed as the ratio of ucOC:cOC-UCR—is positively and statistically significantly correlated with lower rate of low-energy fracture incidence. Full article

(This article belongs to the Special Issue Vitamin K in Human Health and Disease)

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12 pages, 467 KiB

Open AccessArticle

Vitamin K Antagonists and Cognitive Decline in Older Adults: A 24-Month Follow-Up

by Antoine Brangier, Guylaine Ferland, Yves Rolland, Jennifer Gautier, Catherine Féart and Cedric Annweiler

Nutrients 2018, 10(6), 666; https://doi.org/10.3390/nu10060666 - 24 May 2018

Cited by 22 | Viewed by 5081

Abstract

Vitamin K participates in brain physiology. This study aimed to determine whether using vitamin K antagonists (VKAs), which interfere with the vitamin K cycle, were (i) cross-sectionally associated with altered cognitive performance, and (ii) independent predictors of cognitive changes in older adults over 24 months. Information was collected on the use of VKAs (i.e., warfarin, acenocoumarol, and fluindione) among 378 geriatric outpatients (mean, 82.3 ± 5.6 years; 60.1% female). Global cognitive performance and executive functions were assessed with Mini-Mental State Examination (MMSE) and Frontal Assessment Battery (FAB) scores, respectively, at baseline and after 12 and 24 months of follow-up. Age, gender, body mass index, mean arterial pressure, disability, gait speed, comorbidities, atrial fibrillation, stroke, carotid artery stenosis, leukoaraiosis grade on computed tomography (CT) scan, psychoactive drugs, antidementia drugs, blood-thinning drugs (i.e., anticoagulants other than VKAs, antiplatelet medications), serum creatinine levels, and vitamin B12 concentrations were considered as potential confounders. Using VKAs was associated with lower (i.e., worse) FAB score at baseline (adjusted β = −2.1, p = 0.026), and with a decrease in FAB score after 24 months (adjusted β = −203.6%, p = 0.010), but not after 12 months (p = 0.659). Using VKAs was not associated with any change in MMSE score at baseline (p = 0.655), after 12 months (p = 0.603), or after 24 months (p = 0.201). In conclusion, we found more severe executive dysfunction at baseline and incident executive decline over 24 months among geriatric patients using VKAs, when compared with their counterparts. Full article

(This article belongs to the Special Issue Vitamin K in Human Health and Disease)

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16 pages, 1076 KiB

Open AccessArticle

Bicuspid Aortic Valve Stenosis and the Effect of Vitamin K2 on Calcification Using ¹⁸F-Sodium Fluoride Positron Emission Tomography/Magnetic Resonance: The BASIK2 Rationale and Trial Design

by Frederique E. C. M. Peeters, Manouk J. W. Van Mourik, Steven J. R. Meex, Jan Bucerius, Simon M. Schalla, Suzanne C. Gerretsen, Casper Mihl, Marc R. Dweck, Leon J. Schurgers, Joachim E. Wildberger, Harry J. G. M. Crijns and Bas L. J. H. Kietselaer

Nutrients 2018, 10(4), 386; https://doi.org/10.3390/nu10040386 - 21 Mar 2018

Cited by 24 | Viewed by 8525

Abstract

BASIK2 is a prospective, double-blind, randomized placebo-controlled trial investigating the effect of vitamin K2 (menaquinone-7;MK7) on imaging measurements of calcification in the bicuspid aortic valve (BAV) and calcific aortic valve stenosis (CAVS). BAV is associated with early development of CAVS. Pathophysiologic mechanisms are incompletely defined, and the only treatment available is valve replacement upon progression to severe symptomatic stenosis. Matrix Gla protein (MGP) inactivity is suggested to be involved in progression. Being a vitamin K dependent protein, supplementation with MK7 is a pharmacological option for activating MGP and intervening in the progression of CAVS. Forty-four subjects with BAV and mild–moderate CAVS will be included in the study, and baseline ¹⁸F-sodiumfluoride (¹⁸F-NaF) positron emission tomography (PET)/ magnetic resonance (MR) and computed tomography (CT) assessments will be performed. Thereafter, subjects will be randomized (1:1) to MK7 (360 mcg/day) or placebo. During an 18-month follow-up period, subjects will visit the hospital every 6 months, undergoing a second ¹⁸F-NaF PET/MR after 6 months and CT after 6 and 18 months. The primary endpoint is the change in PET/MR ¹⁸F-NaF uptake (6 months minus baseline) compared to this delta change in the placebo arm. The main secondary endpoints are changes in calcium score (CT), progression of the left ventricularremodeling response and CAVS severity (echocardiography). We will also examine the association between early calcification activity (PET) and later changes in calcium score (CT). Full article

(This article belongs to the Special Issue Vitamin K in Human Health and Disease)

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11 pages, 884 KiB

Open AccessArticle

Desphospho-Uncarboxylated Matrix-Gla Protein Is Increased Postoperatively in Cardiovascular Risk Patients

by Sofia Dahlberg, Jacob Ede, Leon Schurgers, Cees Vermeer, Thomas Kander, Bengt Klarin and Ulf Schött

Nutrients 2018, 10(1), 46; https://doi.org/10.3390/nu10010046 - 5 Jan 2018

Cited by 10 | Viewed by 5890

Abstract

Background: Matrix Gla protein (MGP) is an extrahepatic protein that is dependent on glutamate carboxylation, a vitamin K-dependent process. Its dysfunctional form, desphospho-uncarboxylated-MGP, has been associated with increased arterial calcification and stiffness. The aim of this study was to measure the degree of postoperative carboxylation of MGP and two other Gla proteins in patients scheduled for abdominal or orthopaedic surgery. Methods: Forty patients undergoing abdominal or orthopaedic surgery were included. Blood samples were collected preoperatively and four days after the surgery. Desphospho-carboxylated MGP (dp-cMGP), desphospho-uncarboxylated MGP (dp-ucMGP), carboxylated osteocalcin (OC) (cOC), uncarboxylated OC (ucOC), and uncarboxylated prothrombin (PIVKA-II) were analysed. Results: Preoperatively, 29 patients had dp-ucMGP levels above the reference values. Patients with pre-existing cardiovascular comorbidities had higher dp-ucMGP preoperatively compared with patients with no record of cardiovascular disease. Postoperatively, this number increased to 36 patients, and median dp-ucMGP levels increased (p < 0.0001) and correlated to a PIVKA-II increase (r = 0.44). On the other hand, dp-cMGP levels did not significantly alter. Decreased levels of ucOC and cOC were seen after surgery (p = 0.017 and p = 0.0033, respectively). Comorbidities, possible nutritional defects, and complications affecting Gla protein activity and function were identified. Conclusions. Dp-ucMGP was high preoperatively, and had further increased postoperatively. This pattern was linked to several comorbidities, possible nutritional defects, and postoperative complications, which motivates further research about potential interactions between perioperative corrective treatments with vitamin K supplements, cardiovascular biomarkers, and incidents of stroke and myocardial infarction events. Full article

(This article belongs to the Special Issue Vitamin K in Human Health and Disease)

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Review

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15 pages, 958 KiB

Open AccessReview

Potential Role for Osteocalcin in the Development of Atherosclerosis and Blood Vessel Disease

by Alexander Tacey, Tawar Qaradakhi, Tara Brennan-Speranza, Alan Hayes, Anthony Zulli and Itamar Levinger

Nutrients 2018, 10(10), 1426; https://doi.org/10.3390/nu10101426 - 4 Oct 2018

Cited by 48 | Viewed by 6667

Abstract

There is increasing evidence for the involvement of the skeleton in the regulation of atherosclerotic vascular disease. Osteocalcin, an osteoblast derived protein, exists in two forms, carboxylated and undercarboxylated osteocalcin. Undercarboxylated osteocalcin has been linked to the regulation of metabolic functions, including glucose and lipid metabolism. Features of atherosclerosis have been associated with circulating osteocalcin; however, this association is often conflicting and unclear. Therefore, the aim of this review is to examine the evidence for a role of osteocalcin in atherosclerosis development and progression, and in particular endothelial dysfunction and vascular calcification. The current literature suggests that undercarboxylated osteocalcin stimulates the phosphoinositide 3-kinase/protein kinase B (PI3K/Akt) signaling pathway to upregulate nitric oxide and nuclear factor kappa β (NF-кβ) in vascular cells, possibly protecting endothelial function and preventing atherogenesis. However, this effect may be mediated by metabolic factors, such as improvements in insulin signaling, rather than through a direct effect on the vasculature. Total osteocalcin is frequently associated with vascular calcification, an association that may occur as a result of vascular cells eliciting an osteogenic phenotype. Whether osteocalcin acts as a mediator or a marker of vascular calcification is currently unclear. As such, further studies that examine each form of osteocalcin are required to elucidate if it is a mediator of atherogenesis, and whether it functions independently of metabolic factors. Full article

(This article belongs to the Special Issue Vitamin K in Human Health and Disease)

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9 pages, 213 KiB

Open AccessReview

The Vitamin K Metabolome in Chronic Kidney Disease

by Mandy E. Turner, Michael A. Adams and Rachel M. Holden

Nutrients 2018, 10(8), 1076; https://doi.org/10.3390/nu10081076 - 12 Aug 2018

Cited by 14 | Viewed by 4753

Abstract

The purpose of this review is to summarize the research to date on the impact of chronic kidney disease (CKD) on the vitamin K metabolome. Vitamin K-dependent proteins contribute to cardiovascular disease (CVD) prevention via the prevention of ectopic mineralization. Sub-clinical vitamin K deficiency is common in CKD patients, and evidence suggests that it may contribute to the CVD burden in this population. Research from animal models suggests that CKD alters tissue measures of the two predominant forms of vitamin K: K_I and MK-4. The expression and/or activity of enzymes that regulate the recycling of vitamin K and the carboxylation of vitamin K-dependent proteins also appear to be altered in CKD. Evidence suggests that statins, a common pharmaceutical prescribed to CKD patients to prevent cardiovascular events, may impact the metabolism of vitamin K and therefore contribute to its relative inefficiency at preventing CVD in this population as kidney disease progresses. Human research on the tissue vitamin K metabolome in CKD patients is lacking. Full article

(This article belongs to the Special Issue Vitamin K in Human Health and Disease)

16 pages, 1756 KiB

Open AccessReview

VKORC1L1, An Enzyme Mediating the Effect of Vitamin K in Liver and Extrahepatic Tissues

by Julie Lacombe and Mathieu Ferron

Nutrients 2018, 10(8), 970; https://doi.org/10.3390/nu10080970 - 26 Jul 2018

Cited by 19 | Viewed by 6614

Abstract

Vitamin K is an essential nutrient involved in the regulation of blood clotting and tissue mineralization. Vitamin K oxidoreductase (VKORC1) converts vitamin K epoxide into reduced vitamin K, which acts as the co-factor for the γ-carboxylation of several proteins, including coagulation factors produced by the liver. VKORC1 is also the pharmacological target of warfarin, a widely used anticoagulant. Vertebrates possess a VKORC1 paralog, VKORC1-like 1 (VKORC1L1), but until very recently, the importance of VKORC1L1 for protein γ-carboxylation and hemostasis in vivo was not clear. Here, we first review the current knowledge on the structure, function and expression pattern of VKORC1L1, including recent data establishing that, in the absence of VKORC1, VKORC1L1 can support vitamin K-dependent carboxylation in the liver during the pre- and perinatal periods in vivo. We then provide original data showing that the partial redundancy between VKORC1 and VKORC1L1 also exists in bone around birth. Recent studies indicate that, in vitro and in cell culture models, VKORC1L1 is less sensitive to warfarin than VKORC1. Genetic evidence is presented here, which supports the notion that VKORC1L1 is not the warfarin-resistant vitamin K quinone reductase present in the liver. In summary, although the exact physiological function of VKORC1L1 remains elusive, the latest findings clearly established that this enzyme is a vitamin K oxidoreductase, which can support γ-carboxylation in vivo. Full article

(This article belongs to the Special Issue Vitamin K in Human Health and Disease)

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20 pages, 293 KiB

Open AccessFeature PaperReview

Undercarboxylated Osteocalcin: Experimental and Human Evidence for a Role in Glucose Homeostasis and Muscle Regulation of Insulin Sensitivity

by Xuzhu Lin, Tara C. Brennan-Speranza, Itamar Levinger and Bu B. Yeap

Nutrients 2018, 10(7), 847; https://doi.org/10.3390/nu10070847 - 29 Jun 2018

Cited by 66 | Viewed by 7734

Abstract

Recent advances have indicated that osteocalcin, and in particular its undercarboxylated form (ucOC), is not only a nutritional biomarker reflective of vitamin K status and an indicator of bone health but also an active hormone that mediates glucose metabolism in experimental studies. This work has been supported by the putative identification of G protein-coupled receptor, class C, group 6, member A (GPRC6A) as a cell surface receptor for ucOC. Of note, ucOC has been associated with diabetes and with cardiovascular risk in epidemiological studies, consistent with a pathophysiological role for ucOC in vivo. Limitations of existing knowledge include uncertainty regarding the underlying mechanisms by which ucOC interacts with GPRC6A to modulate metabolic and cardiovascular outcomes, technical issues with commonly used assays for ucOC in serum, and a paucity of clinical trials to prove causation and illuminate the scope for novel health interventions. A key emerging area of research is the role of ucOC in relation to expression of GPRC6A in muscle, and whether exercise interventions may modulate metabolic outcomes favorably in part via ucOC. Further research is warranted to clarify potential direct and indirect roles for ucOC in human health and cardiometabolic diseases. Full article

(This article belongs to the Special Issue Vitamin K in Human Health and Disease)

18 pages, 699 KiB

Open AccessFeature PaperReview

Is Matrix Gla Protein Associated with Vascular Calcification? A Systematic Review

by Hilary Barrett, Mary O’Keeffe, Eamon Kavanagh, Michael Walsh and Eibhlís M. O’Connor

Nutrients 2018, 10(4), 415; https://doi.org/10.3390/nu10040415 - 27 Mar 2018

Cited by 68 | Viewed by 9863

Abstract

Specific patient cohorts are at increased risk of vascular calcification. Functional matrix-gla protein (MGP), a tissue-derived vitamin K dependent protein, is reported to be an important inhibitor of vascular calcification and may have clinical potential to modify the progression of vascular calcification through regulation of functional MGP fractions. This systematic review examines twenty-eight studies which assess the relationship between circulating protein expressions of MGP species and vascular calcification in different arterial beds. The included studies examined participants with atherosclerosis, chronic kidney disease (CKD), diabetes, healthy participants, vitamin K supplementation, measured plasma vitamin K levels and vitamin K antagonist usage. The current review reports conflicting results regarding MGP fractions with respect to local calcification development indicating that a multifaceted relationship exists between the MGP and calcification. A primary concern regarding the studies in this review is the large degree of variability in the calcification location assessed and the fraction of MGP measured. This review suggests that different underlying molecular mechanisms can accelerate local disease progression within the vasculature, and specific circulating fractions of MGP may be influenced differently depending on the local disease states related to vascular calcification development. Further studies examining the influence of non-functional MGP levels, with respect to specific calcified arterial beds, are warranted. Full article

(This article belongs to the Special Issue Vitamin K in Human Health and Disease)

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