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Article ; Online: A New Horizon in Vitamin K Research.

Okano, Toshio

Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan

2016 Volume 136, Issue 8, Page(s) 1141–1159

Abstract: Vitamin K is a cofactor for γ-glutamyl carboxylase, which catalyzes the posttranslational conversion of specific glutamyl residues to γ-carboxyglutamyl residues in a variety of vitamin K-dependent proteins (VKDPs) involved in blood coagulation, bone and ... ...

Abstract	Vitamin K is a cofactor for γ-glutamyl carboxylase, which catalyzes the posttranslational conversion of specific glutamyl residues to γ-carboxyglutamyl residues in a variety of vitamin K-dependent proteins (VKDPs) involved in blood coagulation, bone and cartilage metabolism, signal transduction, and cell proliferation. Despite the great advances in the genetic, structural, and functional studies of VKDPs as well as the enzymes identified as part of the vitamin K cycle which enable it to be repeatedly recycled within the cells, little is known of the identity and roles of key regulators of vitamin K metabolism in mammals and humans. This review focuses on new insights into the molecular mechanisms underlying the intestinal absorption and in vivo tissue conversion of vitamin K1 to menaquinone-4 (MK-4) with special emphasis on two major advances in the studies of intestinal vitamin K transporters in enterocytes and a tissue MK-4 biosynthetic enzyme UbiA prenyltransferase domain-containing protein 1 (UBIAD1), which participates in the in vivo conversion of a fraction of dietary vitamin K1 to MK-4 in mammals and humans, although it remains uncertain whether UBIAD1 functions as a key regulator of intracellular cholesterol metabolism, bladder and prostate tumor cell progression, vascular integrity, and protection from oxidative stress.
MeSH term(s)	Animals ; Cell Transformation, Neoplastic/drug effects ; Cholesterol/metabolism ; Dimethylallyltranstransferase/chemistry ; Dimethylallyltranstransferase/metabolism ; Dimethylallyltranstransferase/pharmacology ; Dimethylallyltranstransferase/physiology ; Enterocytes/metabolism ; Humans ; Intestinal Absorption ; Mice ; Neoplasms/pathology ; Oxidative Stress/drug effects ; Vitamin K/metabolism ; Vitamin K/physiology ; Vitamin K 2/analogs & derivatives ; Vitamin K 2/metabolism
Chemical Substances	Vitamin K 2 (11032-49-8) ; Vitamin K (12001-79-5) ; menatetrenone (27Y876D139) ; Cholesterol (97C5T2UQ7J) ; Dimethylallyltranstransferase (EC 2.5.1.1) ; UBIAD1 protein, human (EC 2.5.1.1.)
Language	Japanese
Publishing date	2016-08-01
Publishing country	Japan
Document type	Journal Article ; Review
ZDB-ID	200514-1
ISSN	1347-5231 ; 0031-6903 ; 0372-7750 ; 0919-2085 ; 0919-2131
ISSN (online)	1347-5231
ISSN	0031-6903 ; 0372-7750 ; 0919-2085 ; 0919-2131
DOI	10.1248/yakushi.16-00014
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Article: [The role of the liver in vitamin D metabolism].

Okano, Toshio

Clinical calcium

2015 Volume 25, Issue 11, Page(s) 1613–1618

Abstract: Vitamin D₃is generated in the skin, and subsequently metabolized to 25OHD₃in the liver and then to 1α,25(OH)2D₃in the kidney, and thereafter, 1α,25(OH)₂D₃exerts its biological functions by regulating gene transcription via binding to nuclear receptor, ... ...

Abstract	Vitamin D₃is generated in the skin, and subsequently metabolized to 25OHD₃in the liver and then to 1α,25(OH)2D₃in the kidney, and thereafter, 1α,25(OH)₂D₃exerts its biological functions by regulating gene transcription via binding to nuclear receptor, VDR in target cells. 1α,25(OH)₂D₃plays a critical role in this vitamin D endocrine system. However, it has become obvious in the recent years that plasma concentrations of 25OHD₃but not 1α,25(OH)₂D₃, significantly associate with the incident risk of life style-related diseases such as osteoporosis and diabetes. Moreover, it appears that 25OHD₃itself acts as a ligand for VDR. Based on the findings that liver is not only the major productive organ for 25OHD₃but also the sole productive organ for DBP which serves to deliver 25OHD₃to tissues and stores 25OHD₃in the blood circulation, it is believed that liver plays important roles in vitamin D metabolism and vitamin D functions. The roles of the liver in vitamin D metabolism including the regulatory mechanism of the expression and activation of a 25OHD₃biosynthetic enzyme, CYP2R1, remain largely unsolved.
MeSH term(s)	Animals ; Biological Transport ; Cholestanetriol 26-Monooxygenase/metabolism ; Diet ; Humans ; Liver/metabolism ; Receptors, Calcitriol/metabolism ; Vitamin D/metabolism
Chemical Substances	Receptors, Calcitriol ; Vitamin D (1406-16-2) ; Cholestanetriol 26-Monooxygenase (EC 1.14.15.15)
Language	Japanese
Publishing date	2015-11
Publishing country	Japan
Document type	Journal Article ; Review
ZDB-ID	2386417-5
ISSN	0917-5857
ISSN	0917-5857
DOI	CliCa151116131618
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Article: [Gla-containing proteins].

Okano, Toshio

Clinical calcium

2014 Volume 24, Issue 2, Page(s) 241–248

Abstract: To date, 16 Gla-containing proteins have been discovered in humans, 7 and 9 of which are involved or not-involved in the blood coagulation cascade, respectively. They have a common feature that the carbon at the γ-position of glutamic acid in the ... ...

Abstract	To date, 16 Gla-containing proteins have been discovered in humans, 7 and 9 of which are involved or not-involved in the blood coagulation cascade, respectively. They have a common feature that the carbon at the γ-position of glutamic acid in the specific amino acid sequence of the protein molecule is carboxylated. γ-Glutamyl carboxylase catalyzes this reaction in the presence of vitamin K as a cofactor. Similar to phosphorylation and glycosylation, γ-carboxylation of the glutamic acid has been thought to be one of the post-translational modification for the activation of proteins. However, undercarboxylated, but not highly carboxylated osteocalcin has been found to exhibit regulatory activities of glucose metabolism and insulin sensitivity in mice, suggesting that there would be more comprehensive mechanisms in the regulation of protein functions by the carboxylation of glutamic acid and the decarboxylation of γ-glutamic acid.
MeSH term(s)	Animals ; Bone and Bones/metabolism ; Carbon-Carbon Ligases/biosynthesis ; Glutamic Acid/genetics ; Glutamic Acid/metabolism ; Humans ; Osteocalcin/chemistry ; Osteocalcin/metabolism ; Protein Processing, Post-Translational/drug effects ; Vitamin K/metabolism
Chemical Substances	Osteocalcin (104982-03-8) ; Vitamin K (12001-79-5) ; Glutamic Acid (3KX376GY7L) ; Carbon-Carbon Ligases (EC 6.4.-) ; glutamyl carboxylase (EC 6.4.-)
Language	Japanese
Publishing date	2014-02
Publishing country	Japan
Document type	English Abstract ; Journal Article ; Review
ZDB-ID	2386417-5
ISSN	0917-5857
ISSN	0917-5857
DOI	CliCa1402241248
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Article: [Bone metabolism and cardiovascular function update. Role of vitamin D in the bone and vascular intercommunication].

Okano, Toshio

Clinical calcium

2014 Volume 24, Issue 7, Page(s) 45–52

Abstract: Vascular calcification, hypertension and cardiac hypertrophy have been often complicated in osteoporotic patients with low bone mass. Since there are many similarities among the processes of bone formation and vascular calcification, vitamin D ... ...

Abstract	Vascular calcification, hypertension and cardiac hypertrophy have been often complicated in osteoporotic patients with low bone mass. Since there are many similarities among the processes of bone formation and vascular calcification, vitamin D insufficiency has been thought to be deeply involved in the pathogenesis of these diseases. Indeed, in animal studies, vitamin D receptor gene knockout mice have been shown to display severe vascular calcification, high blood pressure, and left ventricular hypertrophy. On the other hand, in clinical studies, active vitamin D restores vascular calcification and improves heart function in dialysis patients. Whether 1,25 (OH) ₂D₃ acts directly on vascular smooth muscle cells and cardiomyocytes or acts indirectly on them via regulating calcium metabolism remains unclear. The elucidation of the role of vitamin D in the bone and vascular intercommunication and its application toward drug development could be an important step forward in the realization of health and longevity society.
MeSH term(s)	Animals ; Bone and Bones/metabolism ; Cardiovascular Diseases/metabolism ; Cell Communication ; Humans ; Hypertension/metabolism ; Osteoporosis/metabolism ; Vascular Calcification/metabolism ; Vitamin D/metabolism
Chemical Substances	Vitamin D (1406-16-2)
Language	Japanese
Publishing date	2014-07
Publishing country	Japan
Document type	English Abstract ; Journal Article
ZDB-ID	2386417-5
ISSN	0917-5857
ISSN	0917-5857
DOI	CliCa140710131020
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Article: [Clinical application of serum 25OHD].

Okano, Toshio

Clinical calcium

2013 Volume 23, Issue 3, Page(s) 377–384

Abstract: Serum 25OHD concentration is considered to be an appropriate measure for judging vitamin D insufficiency/sufficiency. It is hard to set its reference value. Nowadays, two reference values, namely 50 nmol/L for prevention of bone fracture and 75 nmol/L ... ...

Abstract	Serum 25OHD concentration is considered to be an appropriate measure for judging vitamin D insufficiency/sufficiency. It is hard to set its reference value. Nowadays, two reference values, namely 50 nmol/L for prevention of bone fracture and 75 nmol/L for lowering serum PTH concentration have been proposed. In the elderly, if the former value is used for the assessment, almost half of the population will be classified as insufficient, while the latter is used, almost all the population will be classified as insufficient. Precise and reliable measurements for serum 25OHD are critical for the clinical use of the reference value and the reimbursement of serum 25OHD measurement with the national health care system are required in the treatment of osteoporosis.
MeSH term(s)	Fractures, Bone/blood ; Fractures, Bone/diagnosis ; Fractures, Bone/drug therapy ; Humans ; Osteoporosis/blood ; Osteoporosis/diagnosis ; Osteoporosis/drug therapy ; Parathyroid Hormone/blood ; Reference Values ; Vitamin D/analogs & derivatives ; Vitamin D/blood ; Vitamin D Deficiency/diagnosis
Chemical Substances	Parathyroid Hormone ; Vitamin D (1406-16-2) ; 25-hydroxyvitamin D (A288AR3C9H)
Language	Japanese
Publishing date	2013-03
Publishing country	Japan
Document type	Journal Article ; Review
ZDB-ID	2386417-5
ISSN	0917-5857
ISSN	0917-5857
DOI	CliCa1303377384
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Article ; Online: Key Pathways and Regulators of Vitamin K Function and Intermediary Metabolism.

Shearer, Martin J / Okano, Toshio

Annual review of nutrition

2018 Volume 38, Page(s) 127–151

Abstract: Vitamin K (VK) is an essential cofactor for the post-translational conversion of peptide-bound glutamate to γ-carboxyglutamate. The resultant vitamin K-dependent proteins are known or postulated to possess a variety of biological functions, chiefly in ... ...

Abstract	Vitamin K (VK) is an essential cofactor for the post-translational conversion of peptide-bound glutamate to γ-carboxyglutamate. The resultant vitamin K-dependent proteins are known or postulated to possess a variety of biological functions, chiefly in the maintenance of hemostasis. The vitamin K cycle is a cellular pathway that drives γ-carboxylation and recycling of VK via γ-carboxyglutamyl carboxylase (GGCX) and vitamin K epoxide reductase (VKOR), respectively. In this review, we show how novel molecular biological approaches are providing new insights into the pathophysiological mechanisms caused by rare mutations of both GGCX and VKOR. We also discuss how other protein regulators influence the intermediary metabolism of VK, first through intestinal absorption and second through a pathway that converts some dietary phylloquinone to menadione, which is prenylated to menaquinone-4 (MK-4) in target tissues by UBIAD1. The contribution of MK-4 synthesis to VK functions is yet to be revealed.
MeSH term(s)	Animals ; Gene Expression Regulation, Enzymologic ; Humans ; Intestinal Absorption/physiology ; Mutation ; Vitamin K/metabolism ; Vitamin K Epoxide Reductases/genetics ; Vitamin K Epoxide Reductases/metabolism
Chemical Substances	Vitamin K (12001-79-5) ; Vitamin K Epoxide Reductases (EC 1.17.4.4)
Language	English
Publishing date	2018-06-01
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	406980-8
ISSN	1545-4312 ; 0199-9885
ISSN (online)	1545-4312
ISSN	0199-9885
DOI	10.1146/annurev-nutr-082117-051741
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Article: [Vitamin D, K and bone mineral density].

Okano, Toshio

Clinical calcium

2005 Volume 15, Issue 9, Page(s) 1489–1494

Abstract: Both vitamin D and vitamin K are essential nutrients for bone health. It is believed that vitamin D deficiency is responsible for rickets in infants and osteomalacia in adults, and chronic vitamin D insufficiency induces hyperparathyroidism and reduces ... ...

Abstract	Both vitamin D and vitamin K are essential nutrients for bone health. It is believed that vitamin D deficiency is responsible for rickets in infants and osteomalacia in adults, and chronic vitamin D insufficiency induces hyperparathyroidism and reduces bone mineral density, resulting in an increased risk of osteoporosis. Vitamin K deficiency is thought to cause impaired activation of bone matrix protein osteocalcin, and reduction of osteoblast function, resulting in impaired bone formation. Recently, we reported that a high prevalence of low vitamin D status (low serum 25-hydroxyvitamin D concentration) . low bone mineral density, and a high prevalence of low vitamin K status (high serum undercarboxylated osteocalcin concentration) . high frequency of bone fracture in elderly women in Japan. However, no correlation between low vitamin K status and low bone mineral density was observed in this subjects.
MeSH term(s)	Aged ; Bone Density/physiology ; Female ; Humans ; Vitamin D/blood ; Vitamin D Deficiency/metabolism ; Vitamin K/blood
Chemical Substances	Vitamin K (12001-79-5) ; Vitamin D (1406-16-2)
Language	Japanese
Publishing date	2005-09
Publishing country	Japan
Document type	English Abstract ; Journal Article ; Review
ZDB-ID	2386417-5
ISSN	0917-5857
ISSN	0917-5857
DOI	CliCa14891500
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Article ; Online: Impact of menaquinone-4 supplementation on coronary artery calcification and arterial stiffness: an open label single arm study.

Ikari, Yuji / Torii, Sho / Shioi, Atsushi / Okano, Toshio

Nutrition journal

2016 Volume 15, Issue 1, Page(s) 53

Abstract: Background: Dietary intake of vitamin K has been reported to reduce coronary artery calcification (CAC) and cardiovascular events. However, it is unknown whether supplemental menaquinone (MK)-4 can reduce CAC or arterial stiffness. To study the effect ... ...

Abstract	Background: Dietary intake of vitamin K has been reported to reduce coronary artery calcification (CAC) and cardiovascular events. However, it is unknown whether supplemental menaquinone (MK)-4 can reduce CAC or arterial stiffness. To study the effect of MK-4 supplementation on CAC and brachial ankle pulse wave velocity (baPWV). Methods: This study is a single arm design to take 45 mg/day MK-4 daily as a therapeutic drug for 1 year. Primary endpoint was CAC score determined using 64-slice multislice CT (Siemens), and the secondary endpoint was baPWV measured before and 1 year after MK-4 therapy. Results: A total of 26 patients were enrolled. The average age was 69 ± 8 years and 65 % were female. Plasma levels of phylloquinone (PK), MK-7, and MK4 were 1.94 ± 1.38 ng/ml, 14.2 ± 11.9 ng/ml and 0.4 ± 2.0 ng/ml, respectively, suggesting that MK-7 was the dominant vitamin K in the studied population. Baseline CAC and baPWV were 513 ± 773 and 1834 ± 289 cm/s, respectively. At 1 year following MK-4 supplementation, the values were 588 ± 872 (+14 %) and 1821 ± 378 cm/s (-0.7 %), respectively. In patients with high PIVKA-2, -18 % annual reduction of baPWV was observed. Conclusion: Despite high dose MK-4 supplementation, CAC increased +14 % annually, but baPWV did not change (-0.7 %). The benefits of MK-4 supplementation were only observed in patients with vitamin K insufficiencies correlated with high PIVKA-2 baseline levels, reducing baPWV but not CAC. Trial registration: This study was registered as UMIN 000002760.
MeSH term(s)	Aged ; Ankle Brachial Index ; Body Mass Index ; Cardiomyopathies/prevention & control ; Coronary Vessels/drug effects ; Coronary Vessels/metabolism ; Dietary Supplements ; Endpoint Determination ; Female ; Hemostatics/administration & dosage ; Humans ; Male ; Middle Aged ; Pilot Projects ; Prospective Studies ; Pulse Wave Analysis ; Risk Factors ; Vascular Stiffness/drug effects ; Vitamin K 1/administration & dosage ; Vitamin K 1/blood ; Vitamin K 2/administration & dosage ; Vitamin K 2/analogs & derivatives ; Vitamin K 2/blood
Chemical Substances	Hemostatics ; Vitamin K 2 (11032-49-8) ; menatetrenone (27Y876D139) ; Vitamin K 1 (84-80-0) ; menaquinone 7 (8427BML8NY)
Language	English
Publishing date	2016-05-12
Publishing country	England
Document type	Journal Article
ZDB-ID	2091602-4
ISSN	1475-2891 ; 1475-2891
ISSN (online)	1475-2891
ISSN	1475-2891
DOI	10.1186/s12937-016-0175-8
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Article: [Recommended daily allowance and dietary reference intakes for vitamin D and calcium in Japanese].

Okano, Toshio

Clinical calcium

2003 Volume 13, Issue 7, Page(s) 876–881

Abstract: In the sixth edition of the recommended dietary allowance (RDA) for Japanese-dietary reference intakes by the Ministry of Health, Labour and Welfare, Japan, RDA and tolerable upper limit (UL) for vitamin D and calcium were set. RDA and UL for calcium ... ...

Abstract	In the sixth edition of the recommended dietary allowance (RDA) for Japanese-dietary reference intakes by the Ministry of Health, Labour and Welfare, Japan, RDA and tolerable upper limit (UL) for vitamin D and calcium were set. RDA and UL for calcium were set on the basis of the calcium balance study and the factorial method. In contrast, plasma 25-hydroxyvitamin D level in subjects as a maker reflecting vitamin D nutrition status was first used for setting the RDA and UL in this edition.
Language	Japanese
Publishing date	2003-07
Publishing country	Japan
Document type	English Abstract ; Journal Article
ZDB-ID	2386417-5
ISSN	0917-5857
ISSN	0917-5857
DOI	CliCa0307876881
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Article: [Vitamin D analogs and calcium metabolism - bone-selective analogs -].

Okano, Toshio

Clinical calcium

2003 Volume 13, Issue 7, Page(s) 911–914

Abstract: 2MD [2-methylene-19-nor- (20S) -1alpha, 25 (OH)(2)D(3)] is a bone-selective vitamin D analog that has been developed on the basis of structure-function study. The bone-selective action of the analog has been tested and confirmed both in vitro and in vivo ...

Abstract	2MD [2-methylene-19-nor- (20S) -1alpha, 25 (OH)(2)D(3)] is a bone-selective vitamin D analog that has been developed on the basis of structure-function study. The bone-selective action of the analog has been tested and confirmed both in vitro and in vivo and its clinical application as a medication for bone diseases is anticipated although its adverse effects remain unclear.
Language	Japanese
Publishing date	2003-07
Publishing country	Japan
Document type	English Abstract ; Journal Article
ZDB-ID	2386417-5
ISSN	0917-5857
ISSN	0917-5857
DOI	CliCa0307911914
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