Vitamin K-dependent carboxylation regulates Ca2+ flux and adaptation to metabolic stress in ß cells.

Vitamin K is a micronutrient necessary for γ-carboxylation of glutamic acids. This post-translational modification occurs in the endoplasmic reticulum (ER) and affects secreted proteins. Recent clinical studies implicate vitamin K in the pathophysiology of diabetes, but the underlying molecular mechanism remains unknown. Here, we show that mouse ß cells lacking γ-carboxylation fail to adapt their insulin secretion in the context of age-related insulin resistance or diet-induced ß cell stress. In human islets, γ-carboxylase expression positively correlates with improved insulin secretion in response to glucose. We identify endoplasmic reticulum Gla protein (ERGP) as a γ-carboxylated ER-resident Ca2+-binding protein expressed in ß cells. Mechanistically, γ-carboxylation of ERGP protects cells against Ca2+ overfilling by diminishing STIM1 and Orai1 interaction and restraining store-operated Ca2+ entry. These results reveal a critical role of vitamin K-dependent carboxylation in regulation of Ca2+ flux in ß cells and in their capacity to adapt to metabolic stress.

Biological Role of Vitamin K-With Particular Emphasis on Cardiovascular and Renal Aspects.

Vitamin K (VK) plays many important functions in the body. The most important of them include the contribution in calcium homeostasis and anticoagulation. Vascular calcification (VC) is one of the most important mechanisms of renal pathology. The most potent inhibitor of this process-matrix Gla protein (MGP) is VK-dependent. Chronic kidney disease (CKD) patients, both non-dialysed and hemodialysed, often have VK deficiency. Elevated uncarboxylated matrix Gla protein (ucMGP) levels indirectly reflected VK deficiency and are associated with a higher risk of cardiovascular events in these patients. It has been suggested that VK intake may reduce the VC and related cardiovascular risk. Vitamin K intake has been suggested to reduce VC and the associated cardiovascular risk. The role and possibility of VK supplementation as well as the impact of anticoagulation therapy on VK deficiency in CKD patients is discussed.

Vitamin K: A vital micronutrient with the cardioprotective potential against diabetes-associated complications.

Cardiovascular disease (CVD) remains the leading cause of mortality in patients with type 2 diabetes (T2D). The conventional therapies seem to offer minimal long-term cardioprotection against diabetes-related complications in patients living with T2D. There is a growing interest in understanding the therapeutic effects of food-derived bioactive compounds in protecting or managing these metabolic diseases. This includes uncovering the therapeutic potential of fat-soluble micronutrients such as vitamin K, which are abundantly found in green leafy vegetables. We searched the major electronic databases including PubMed, Web of Sciences, Scopus, Google Scholar and Science direct. The search retrieved randomized clinical trials and preclinical studies, reporting on the impact of vitamin K on CVD-related complications in T2D. The current review updates clinical evidence on the therapeutic benefits of vitamin K by attenuating CVD-risk factors such as blood lipid profiles, blood pressure, as well as markers of oxidative stress and inflammation in patients with T2D. Importantly, the summarized preclinical evidence provides a unique perspective into the pathophysiological mechanisms that could be targeted by vitamin K in the primary prevention of T2D-related complications. Lastly, this review further explores the controversies related to the cardioprotective effects of vitamin K, and also provides the basic information such as the source and bioavailability profile of this micronutrient is covered to highlight its therapeutic potential.

The Role of Vitamin K in Cholestatic Liver Disease.

Vitamin K (VK) is a ligand of the pregnane X receptor (PXR), which plays a critical role in the detoxification of xenobiotics and metabolism of bile acids. VK1 may reduce the risk of death in patients with chronic liver failure. VK deficiency is associated with intrahepatic cholestasis, and is already being used as a drug for cholestasis-induced liver fibrosis in China. In Japan, to treat osteoporosis in patients with primary biliary cholangitis, VK2 formulations are prescribed, along with vitamin D3. Animal studies have revealed that after bile duct ligation-induced cholestasis, PXR knockout mice manifested more hepatic damage than wild-type mice. Ligand-mediated activation of PXR improves biochemical parameters. Rifampicin is a well-known human PXR ligand that has been used to treat intractable pruritus in severe cholestasis. In addition to its anti-cholestatic properties, PXR has anti-fibrotic and anti-inflammatory effects. However, because of the scarcity of animal studies, the mechanism of the effect of VK on cholestasis-related liver disease has not yet been revealed. Moreover, the application of VK in cholestasis-related diseases is controversial. Considering this background, the present review focuses on the effect of VK in cholestasis-related diseases, emphasizing its function as a modulator of PXR.

[Diseases Due to the Deficiency in Vitamin K Conversion System and Its Prevention].

Vitamin K is a fat-soluble vitamin that plays an important role in blood coagulation and bone formation. Vitamin K has homologues due to differences in the side chain structure, phylloquinone (abbreviated as vitamin K1, PK) having a phytyl side chain and menaquinones (MK-n, n=1 to 14) having an isoprenoid side chain structure. The main vitamin K that we take from our daily diet is PK, and a fermented food, natto, contains MK-7 produced by Bacillus subtilis natto. However, the majority of vitamin K present in the tissues of mammals, including humans, is menaquinone-4 (abbreviated as vitamin K2, MK-4) having a geranylgeranyl side chain. This reason is that PK or MK-n obtained in the diet is converted into MK-4 in the body. We identified that the UbiA prenyltransferase domain containing protein 1 (UBIAD1) is the conversion enzyme of PK and MK-n to MK-4. The physiological roles of MK-4 in all tissues of the whole body and the physiological significance of MK-4 converted from PK and MK-n by UBIAD1 have not been sufficiently elucidated yet. To investigate the function of UBIAD1 in vivo, we generated UBIAD1 systemic knockout mice and tissue-specific UBIAD1 knockout mice. In this paper, we introduce the usefulness of vitamin K for diseases that may involve vitamin K and UBIAD1.

γ-Glutamyl carboxylase mutations differentially affect the biological function of vitamin K-dependent proteins.

γ-Glutamyl carboxylase (GGCX) is an integral membrane protein that catalyzes posttranslational carboxylation of a number of vitamin K-dependent (VKD) proteins involved in a wide variety of physiologic processes, including blood coagulation, vascular calcification, and bone metabolism. Naturally occurring GGCX mutations are associated with multiple distinct clinical phenotypes. However, the genotype-phenotype correlation of GGCX remains elusive. Here, we systematically examined the effect of all naturally occurring GGCX mutations on the carboxylation of 3 structure-function distinct VKD proteins in a cellular environment. GGCX mutations were transiently introduced into GGCX-deficient human embryonic kidney 293 cells stably expressing chimeric coagulation factor, matrix Gla protein (MGP), or osteocalcin as VKD reporter proteins, and then the carboxylation efficiency of these reporter proteins was evaluated. Our results show that GGCX mutations differentially affect the carboxylation of these reporter proteins and the efficiency of using vitamin K as a cofactor. Carboxylation of these reporter proteins by a C-terminal truncation mutation (R704X) implies that GGCX's C terminus plays a critical role in the binding of osteocalcin but not in the binding of coagulation factors and MGP. This has been confirmed by probing the protein-protein interaction between GGCX and its protein substrates in live cells using bimolecular fluorescence complementation and chemical cross-linking assays. Additionally, using a minigene splicing assay, we demonstrated that several GGCX missense mutations affect GGCX's pre-messenger RNA splicing rather than altering the corresponding amino acid residues. Results from this study interpreted the correlation of GGCX's genotype and its clinical phenotypes and clarified why vitamin K administration rectified bleeding disorders but not nonbleeding disorders.

Beneficial Effects of Vitamin K Status on Glycemic Regulation and Diabetes Mellitus: A Mini-Review.

Type 2 diabetes mellitus is a chronic disease that is characterized by hyperglycemia, insulin resistance, and dysfunctional insulin secretion. Glycemic control remains a crucial contributor to the progression of type 2 diabetes mellitus as well as the prevention or delay in the onset of diabetes-related complications. Vitamin K is a fat-soluble vitamin that plays an important role in the regulation of the glycemic status. Supplementation of vitamin K may reduce the risk of diabetes mellitus and improve insulin sensitivity. This mini-review summarizes the recent insights into the beneficial effects of vitamin K and its possible mechanism of action on insulin sensitivity and glycemic status, thereby suppressing the progression of diabetes mellitus.

Endocrine roles of vitamin K-dependent- osteocalcin in the relation between bone metabolism and metabolic disorders.

Obesity and diabetes are important metabolic diseases and a major public health problem among the world, they have serious health and economic complications. Overweight and obesity are increased risk for deficiency of vitamin particularly shortage of fat soluble-vitamins. Studies reported that vitamin K supplementation reduces oxidative stress and metabolic risk biomarkers for diabetes, as well as reduces progression of insulin resistance. Vitamin K-dependent-protein osteocalcin (bone derived hormone) plays crucial roles in energy metabolism. There is a clear association between circulating vitamin k and dependent-osteocalcin concentrations with obesity and risk of Type 2 diabetes. Osteocalcin through molecular mechanisms improves insulin resistance, lipid and glucose profile, and mediate vitamin K positive effects. Insulin also signals osteocalcin to regulate bone mineralization. Normal carboxylation of vitamin K-dependent proteins/ hormones is a key step in preventing apoptosis and calcification of vascular endothelial cells. A missing relationship between bone, glucose and fat metabolism could clarify and manage many metabolic mechanisms. This review focuses on the physiological relationship between vitamin K-dependent-osteocalcin, metabolic and cardiovascular diseases through some molecular proteins and hormones including adipokines. A better understanding of the mechanism of action of osteocalcin modulated by vitamin K could help in implementing therapeutic drugs to cure metabolic diseases.

Vitamin K and cystic fibrosis: A gordian knot that deserves our attention.

Cystic fibrosis (CF) is an inherited genetic disorder with multiorgan involvement. Gastrointestinal tract dysfunction leads to fat and fat-soluble vitamins (A,D,E,K) malabsorption and deficiency of these vitamins. Subclinical vitamin K (VK) deficiency seems to be a common problem in CF patients. However, despite the rest of fat-soluble vitamins being routinely supplemented, this is not a universal clinical practice for VK. Inefficient levels of VK may have significant effects on blood coagulation and bone formation. There are also some data indicating that VK may play a key role on regulation of inflammation. Supplementing CF patients with VK seems rational, but the appropriate dosing regimens are still a matter of debate. This review will try to delineate the problem and communicate the latest opinions on this controversial issue.

Role of Vascular Smooth Muscle Cell Phenotypic Switching and Calcification in Aortic Aneurysm Formation.

Aortic aneurysm is a vascular disease whereby the ECM (extracellular matrix) of a blood vessel degenerates, leading to dilation and eventually vessel wall rupture. Recently, it was shown that calcification of the vessel wall is involved in both the initiation and progression of aneurysms. Changes in aortic wall structure that lead to aneurysm formation and vascular calcification are actively mediated by vascular smooth muscle cells. Vascular smooth muscle cells in a healthy vessel wall are termed contractile as they maintain vascular tone and remain quiescent. However, in pathological conditions they can dedifferentiate into a synthetic phenotype, whereby they secrete extracellular vesicles, proliferate, and migrate to repair injury. This process is called phenotypic switching and is often the first step in vascular pathology. Additionally, healthy vascular smooth muscle cells synthesize VKDPs (vitamin K-dependent proteins), which are involved in inhibition of vascular calcification. The metabolism of these proteins is known to be disrupted in vascular pathologies. In this review, we summarize the current literature on vascular smooth muscle cell phenotypic switching and vascular calcification in relation to aneurysm. Moreover, we address the role of vitamin K and VKDPs that are involved in vascular calcification and aneurysm. Visual Overview- An online visual overview is available for this article.

A potential biotechnological process for the sustainable production of vitamin K1.

The primary objective of this review is to propose an approach for the biosynthesis of phylloquinone (vitamin K1) based upon its known sources, its role in photosynthesis and its biosynthetic pathway. The chemistry, health benefits, market, and industrial production of vitamin K are also summarized. Vitamin K compounds (K vitamers) are required for the normal function of at least 15 proteins involved in diverse physiological processes such as coagulation, tissue mineralization, inflammation, and neuroprotection. Vitamin K is essential for the prevention of Vitamin K Deficiency Bleeding (VKDB), especially in neonates. Increased vitamin K intake may also reduce the severity and/or risk of bone fracture, arterial calcification, inflammatory diseases, and cognitive decline. Consumers are increasingly favoring natural food and therapeutic products. However, the bulk of vitamin K products employed for both human and animal use are chemically synthesized. Biosynthesis of the menaquinones (vitamin K2) has been extensively researched. However, published research on the biotechnological production of phylloquinone is restricted to a handful of available articles and patents. We have found that microalgae are more suitable than plant cell cultures for the biosynthesis of phylloquinone. Many algae are richer in vitamin K1 than terrestrial plants, and algal cells are easier to manipulate. Vitamin K1 can be efficiently recovered from the biomass using supercritical carbon dioxide extraction.

Circulating small non-coding RNAs provide new insights into vitamin K nutrition and reproductive physiology in teleost fish.

BACKGROUND: Vitamin K (VK) is a fat-soluble vitamin known for its essential role in blood coagulation, but also on other biological processes (e.g. reproduction, brain and bone development) have been recently suggested. Nevertheless, the molecular mechanisms behind its particular function on reproduction are not yet fully understood. METHODS: The potential role of VK on reproduction through nutritional supplementation in Senegalese sole (Solea senegalensis) was assessed by gonadal maturation and 11-ketosterone, testosterone and estriol plasma levels when fed with control or VK supplemented (1250 mg kg-1 of VK1) diets along a six month trial. At the end, sperm production and quality (viability and DNA fragmentation) were evaluated. Circulating small non-coding RNAs (sncRNAs) in blood plasma from males were also studied through RNA-Seq. RESULTS: Fish fed with dietary VK supplementation had increased testosterone levels and lower sperm DNA fragmentation. SncRNAs from blood plasma were found differentially expressed when nutritional and sperm quality conditions were compared. PiR-675//676//4794//5462 and piR-74614 were found up-regulated in males fed with dietary VK supplementation. Let-7g, let-7e(18nt), let-7a-1, let-7a-3//7a-2//7a-1, let-7e(23nt) and piR-675//676//4794//5462 were found to be up-regulated and miR-146a and miR-146a-1//146a-2//146a-3 down-regulated when fish with low and high sperm DNA fragmentation were compared. Bioinformatic analyses of predicted mRNAs targeted by sncRNAs revealed the potential underlying pathways. CONCLUSIONS: VK supplementation improves fish gonad maturation and sperm quality, suggesting an unexpected and complex regulation of the nutritional status and reproductive performance through circulating sncRNAs. GENERAL SIGNIFICANCE: The use of circulating sncRNAs as reliable and less-invasive physiological biomarkers in fish nutrition and reproduction has been unveiled.

Vitamin K Status, Warfarin Use, and Arterial Stiffness in Heart Failure.

Large artery stiffening contributes to the pathophysiology of heart failure (HF) and associated comorbidities. MGP (matrix Gla-protein) is a potent inhibitor of vascular calcification. MGP activation is vitamin K-dependent. We aimed (1) to compare dp-ucMGP (dephospho-uncarboxylated MGP) levels between subjects with HF with preserved ejection fraction (HFpEF) and HF with reduced ejection fraction (HFrEF) and subjects without HF; (2) to assess the relationship between dp-ucMGP levels and arterial stiffness; and (3) to assess the relationship between warfarin use, dp-ucMGP levels, and arterial stiffness in HF. We enrolled 348 subjects with HFpEF (n=96), HFrEF (n=53), or no HF (n=199). Carotid-femoral pulse wave velocity, a measure of large artery stiffness, was measured with arterial tonometry. Dp-ucMGP was measured with ELISA. Dp-ucMGP levels were greater in both HFrEF (582 pmol/L; 95% CI, 444-721 pmol/L) and HFpEF (549 pmol/L; 95% CI, 455-643 pmol/L) compared with controls (426 pmol/L; 95% CI, 377-475 pmol/L; ANCOVA P=0.0067). Levels of dp-ucMGP were positively associated with carotid-femoral pulse wave velocity (standardized ß, 0.31; 95% CI, 0.19-0.42; P<0.0001), which was also true in analyses restricted to patients with HF (standardized ß, 0.34; 95% CI, 0.16-0.52; P=0.0002). Warfarin use was significantly associated with carotid-femoral pulse wave velocity (standardized ß, 0.13; 95% CI, 0.004-0.26; P=0.043), but this relationship was eliminated after adjustment for dp-ucMGP. In conclusion, levels of dp-ucMGP are increased in HFpEF and HFrEF and are independently associated with arterial stiffness. Future studies should investigate whether vitamin K supplementation represents a suitable therapeutic strategy to prevent or reduce arterial stiffness in HFpEF and HFrEF.

Vitamin K and Bone Metabolism: A Review of the Latest Evidence in Preclinical Studies.

Bone is a metabolically active tissue that renews itself throughout one's life. Cytokines along with several hormonal, nutritional, and growth factors are involved in tightly regulated bone remodeling. Accordingly, vitamin K as a multifunctional vitamin has been recently deemed appreciable as a topic of research as it plays a pivotal role in maintenance of the bone strength, and it has been proved to have a positive impact on the bone metabolism. Vitamin K exerts its anabolic effect on the bone turnover in different ways such as promoting osteoblast differentiation, upregulating transcription of specific genes in osteoblasts, and activating the bone-associated vitamin k dependent proteins which play critical roles in extracellular bone matrix mineralization. There is also credible evidence to support the effects of vitamin k2 on differentiation of other mesenchymal stem cells into osteoblast. The main objective of the present paper is to comprehensively outline the preclinical studies on the properties of vitamin K and its effects on the bone metabolism. The evidence could shed light on further clinical studies to improve osteogenesis in bone graft surgeries.

The role of TAM family receptors and ligands in the nervous system: From development to pathobiology.

Tyro3, Axl, and Mertk, referred to as the TAM family of receptor tyrosine kinases, are instrumental in maintaining cell survival and homeostasis in mammals. TAM receptors interact with multiple signaling molecules to regulate cell migration, survival, phagocytosis and clearance of metabolic products and cell debris called efferocytosis. The TAMs also function as rheostats to reduce the expression of proinflammatory molecules and prevent autoimmunity. All three TAM receptors are activated in a concentration-dependent manner by the vitamin K-dependent growth arrest-specific protein 6 (Gas6). Gas6 and the TAMs are abundantly expressed in the nervous system. Gas6, secreted by neurons and endothelial cells, is the sole ligand for Axl. ProteinS1 (ProS1), another vitamin K-dependent protein functions mainly as an anti-coagulant, and independent of this function can activate Tyro3 and Mertk, but not Axl. This review will focus on the role of the TAM receptors and their ligands in the nervous system. We highlight studies that explore the function of TAM signaling in myelination, the visual cortex, neural cancers, and multiple sclerosis (MS) using Gas6-/- and TAM mutant mice models.

Vitamin K and cancer.

Subclinical vitamin K deficits refer to carboxylation defects of different types of vitamin K-dependent hepatic and extrahepatic so-called Gla proteins without prolongation of the prothrombin time. This condition has been reported in different clinical situations due to insufficient supply or malabsorption of vitamin K as well as drug interactions. This review discusses the effects of different vitamin K subspecies on tumour growth and the possible anti-tumour effects of increased vitamin K intake. Blocking carboxylation of vitamin K-dependent proteins with warfarin anticoagulation - what are the risks/benefits for carcinogenesis? Previous studies on both heparin and low molecular weight heparin blocking of the vitamin K-dependent factors X and II have shown tumour suppressive effects. Vitamin K has anti-inflammatory effects that could also impact carcinogenesis, but little data exists on this subject.

Vitamin K and osteoporosis: Myth or reality?

Vitamin K is a liposoluble vitamin. The predominant dietary form, phylloquinone or vitamin K1, is found in plants and green vegetables; whereas menaquinone, or vitamin K2, is endogenously synthesized by intestinal bacteria and includes several subtypes that differ in side chain length. Aside from its established role in blood clotting, several studies now support a critical function of vitamin K in improving bone health. Vitamin K is in fact required for osteocalcin carboxylation that in turn regulates bone mineral accretion; it seems to promote the transition of osteoblasts to osteocytes and also limits the process of osteoclastogenesis. Several observational and interventional studies have examined the relationship between vitamin K and bone metabolism, but findings are conflicting and unclear. This systematic review aims to investigate the impact of vitamin K (plasma levels, dietary intake, and oral supplementation) on bone health with a particular interest in bone remodeling, mineral density and fragility fractures.

A guide to acquired vitamin K coagulophathy diagnosis and treatment: the Russian perspective.

Physicians often come across with cases of vitamin K antagonists-dependent coagulopathy for reasons such as accidental use of the vitamin K antagonists (VKA), excessive administration of prescribed anticoagulants of indirect action or not reported administration of vitamin K antagonists due to memory impairment and/or other mental disorders, even deliberate use thereof (attempt to murder or suicide). Rodenticide-poisoning (coumarins, warfarins) via food or occupational accidents are difficult to diagnose. This article discusses different types of acquired vitamin K-dependent coagulopathy. Differential diagnosis is primarily based on patient statements before additional causes of vitamin K deficiency are explored. Even when pathological vitamin K deficiency is not determined, appropriate and urgent medical treatment is necessary: administration of fresh frozen plasma or concentrated factors of the prothrombin complex, administration of vitamin K remedies along with symptomatic therapy. With early diagnosis and prescription of appropriate therapy, prognosis is favorable. Reasons for vitamin K antagonists-dependent coagulopathy cases.

Vitamin K-Dependent Carboxylation of Matrix Gla Protein Influences the Risk of Calciphylaxis.

Matrix Gla protein (MGP) is a potent inhibitor of vascular calcification. The ability of MGP to inhibit calcification requires the activity of a vitamin K-dependent enzyme, which mediates MGP carboxylation. We investigated how MGP carboxylation influences the risk of calciphylaxis in adult patients receiving dialysis and examined the effects of vitamin K deficiency on MGP carboxylation. Our study included 20 patients receiving hemodialysis with calciphylaxis (cases) and 20 patients receiving hemodialysis without calciphylaxis (controls) matched for age, sex, race, and warfarin use. Cases had higher plasma levels of uncarboxylated MGP (ucMGP) and carboxylated MGP (cMGP) than controls. However, the fraction of total MGP that was carboxylated (relative cMGP concentration = cMGP/[cMGP + uncarboxylated MGP]) was lower in cases than in controls (0.58±0.02 versus 0.69±0.03, respectively; P=0.003). In patients not taking warfarin, cases had a similarly lower relative cMGP concentration. Each 0.1 unit reduction in relative cMGP concentration associated with a more than two-fold increase in calciphylaxis risk. Vitamin K deficiency associated with lower relative cMGP concentration in multivariable adjusted analyses (ß=-8.99; P=0.04). In conclusion, vitamin K deficiency-mediated reduction in relative cMGP concentration may have a role in the pathogenesis of calciphylaxis. Whether vitamin K supplementation can prevent and/or treat calciphylaxis requires further study.

Effect of vitamin K in bone metabolism and vascular calcification: A review of mechanisms of action and evidences.

Osteoporosis is a public health concern associated with an increased risk of bone fractures and vascular calcification. Vitamin K presents unique benefits on these issues, although understudied. The two main forms of vitamin K are phylloquinone (vitamin K1) and menaquinone (vitamin K2). In this study, it was especially investigated the action of vitamin K2 in bones and vessels. Vitamin K2 has shown to stimulate bone formation by promoting osteoblast differentiation and carboxylation of osteocalcin, and increasing alkaline phosphatase, insulin-like growth factor-1, growth differentiation factor-15, and stanniocalcin 2 levels. Furthermore, vitamin K2 reduces the pro-apoptotic proteins Fas and Bax in osteoblasts, and decreases osteoclast differentiation by increasing osteoprotegerin and reducing the receptor activator of nuclear factor kappa-B ligand. In blood vessels, vitamin K2 reduces the formation of hydroxyapatite, through the carboxylation of matrix Gla protein and Gla rich protein, inhibits the apoptosis of vascular smooth muscle cells, by increasing growth arrest-specific gene 6, and reduces the transdifferentiation of vascular smooth muscle cells to osteoblasts. The commonly used dosage of vitamin K2 in human studies is 45 mg/day and its application can be an interesting strategy in benefitting bone and vascular health, especially to osteoporotic post-menopausal women.