**Author details**

Mona Møller1 \*, Serena Tonstad<sup>2</sup> , Tone Bathen3 and Jan Oxholm Gordeladze4


#### **References**


**Author details**

1 KappaBio, Oslo, Norway

94 Vitamin K2 - Vital for Health and Wellbeing

2 Ullevål Hospital, Oslo, Norway

4 University of Oslo, Oslo, Norway

*Cell*. **131** (2007) 242–256.

3 NTNU, Trondheim, Norway

\*, Serena Tonstad<sup>2</sup>

\*Address all correspondence to: mona.moller@kappabio.com

, Tone Bathen3

OGT Glycosylates a substantial and diverse amount of proteins, encompassing species like histone

PFKFB1 Encodes a member of the family of the bifunctional 6-phophofructo-2 kinase: fructose-2,

alternatively spliced transcript variants have been found for this gene. PTPN11 PTP (protein tyrosine phosphatase) is a member a large family of phosphatases and plays a

SLC16A2 Very active and specific thyroid hormone transporter molecule. Stimulates cellular uptake of

H2B, AKT1 and PFK (phosphofructokinase). It can modulate their cellular processes through cross-talk between processes like glycosylation and phosphorylation, or via proteolytic processing. Involved in insulin sensitivity in muscle cells and adipocytes by glycosylating components of insulin signaling, blocks phosphorylation of AKT1, stimulates IRS1

phosphorylation, as well as attenuating insulin signaling. *Interpretation:* Modulator of insulin and IGF-1 signaling/sensitivity to maintain a healthy muscle tissue fat mass and distribution.

regulatory role in various cell signaling events that are important for a diversity of cell functions, such as mitogenic activation, metabolic control, transcription regulation, and cell migration. *Interpretation:* Because of the activating effects of PTPN11 on ERK (extracellular signal regulated kinase), a lack of PTPN11 activation may lead to adiposity, diabetes, and hyperleptinemia.

thyroxine (T4), triiodothyronine (T3), reverse triiodothyronine (rT3), and diiodothyronine. *Interpretation:* Lack of SLC16A2 activation may lead to a reduction in uptake and biological functions of T4 and T3, which is associated with adiposity, diabetes, and hyperleptinemia.

6-bisphosphatase enzymes. These enzymes form homodimers, which catalyze the synthesis, as well as the degradation of fructose 2, 6-bishosphate, via independent catalytic domains. Fructose-2, 6-bisphosphate serves as the activator of the glycolytic pathway, and as the inhibitor of the gluconeogenetic pathway. *Interpretation:* Regulating fructose-2,6-bisphosphate levels through the activity of this enzyme is thought to regulate glucose homeostasis. Multiple

[1] Virtanen KA, Lidell ME, Orava J, Heglind M, Westergren R, Niemi T, Taittonen M, Laine J, Savisto NJ, Enerback S, et al. Different metabolic responses of human brown adipose

[2] Gesta S, Tseng YH, Kahn CR. Developmental origin of fat: tracking obesity to its source.

tissue to activation by cold and insulin. *Engl. N. Med. J*. **360** (2009) 1518–1525.

and Jan Oxholm Gordeladze4

Mona Møller1

**References**


[28] Bügel S ,Vitamin K, and bone health in adult humans. *Vitam. Horm*. **78** (2008) 393–416.

*Rev*. **69**(10); (2011) 584–598. doi: 10.1111/j.1753-4887.2011.00372.x.

pregnane X receptor. *Toxicol. Sci*. **82** (2004) 374–380.

expression. *Annu. Rev. Biochem*. **66** (1997) 581–611.

liver. *J. Biol. Chem*. **282** (2007) 9768–9776.

*Endocrinol. Metab*. **284** (2003) E671–E678.

coactivator PGC-1. *Nature*. **413** (2001) 179–183.

*Trends Endocrinol. Metab*. **16** (2005) 183–189.

activity. *J. Biol. Chem*. **275** (2000) 36324–36333.

into insulin action. *Nat. Rev. Mol. Cell Biol*. **7** (2006) 85–96.

(2009) 1611–1621.

15013–15020.

513–532.

[29] Ahmadieh H, Arabi A. Vitamins and bone health: beyond calcium and vitamin D. *Nutr* 

The Impact of Vitamin K2 on Energy Metabolism

http://dx.doi.org/10.5772/67152

97

[30] Cheng J, Ma X, Krausz KW, et al. Rifampicin-activated human pregnane X receptor and CYP3A4 induction enhance acetaminopheninduced toxicity. *Drug Metab. Dispos*. **37**

[31] Guo GL, Moffit JS, Nicol CJ, et al. Enhanced acetaminophen toxicity by activation of the

[32] Nakamura K, Moore R, Negishi M, Sueyoshi T. Nuclear pregnane X receptor cross-talk with FoxA2 to mediate drug-induced regulation of lipid metabolism in fasting mouse

[33] Zhou J, Zhai Y, Mu Y, et al. A novel pregnane X receptormediated and sterol regulatory element-binding protein-independent lipogenic pathway. *J. Biol. Chem*. **281** (2006)

[34] Hanson RW, Reshef L. Regulation of phosphoenolpyruvate carboxykinase (GTP) gene

[35] Jiang G, Zhang BB. Glucagon and regulation of glucose metabolism. *Am. J. Physiol.* 

[36] van Schaftingen E, Gerin I. The glucose-6-phosphatase system. *Biochem*. J. **362** (2002)

[37] Gonzalez GA, Montminy MR. Cyclic AMP stimulates somatostatin gene transcription

[38] Herzig S, Long F, Jhala US, et al. CREB regulates hepatic gluconeogenesis through the

[39] Taniguchi CM, Emanuelli B, Kahn CR. Critical nodes in signalling pathways: Insights

[40] Barthel A, Schmoll D, Unterman TG. FoxO proteins in insulin action and metabolism.

[41] Matsuzaki H, Daitoku H, Hatta M, et al. Acetylation of Foxo1 alters its DNA-binding ability and sensitivity to phosphorylation. *Proc. Natl. Acad. Sci. USA*. **102** (2005) 11278–11283.

[42] Schmoll D, Walker KS, Alessi DR, et al. Regulation of glucose-6-phosphatase gene expression by protein kinase Ba and the forkhead transcription factor FKHR. Evidence for insulin response unit-dependent and independent effects of insulin on promoter

[43] Louet JF, Le May C, Pegorier JP, et al. Regulation of liver carnitine palmitoyltransferase I gene expression by hormones and fatty acids. *Biochem. Soc. Trans*. **29** (2001) 310–316.

by phosphorylation of CREB at serine 133. *Cell*. **59** (1989) 675–680.


[28] Bügel S ,Vitamin K, and bone health in adult humans. *Vitam. Horm*. **78** (2008) 393–416.

[15] Compston J. Obesity and bone. *Curr*. *Osteoporos*. *Rep*. **11** (2013) 30–35.

biotic metabolism. *Nucl. Recept. Signal*. **7** (2009) 1–21.

enzymes. *Mol. Cell. Biol*. **24** (2004) 7931–40.

enzymes. *Mol. Cell. Biol*. **24** (2004) 7931–7940.

Metabolism. *Ann. Rev. Physiol*. **65** (2003) 261–311.

*Biochem. J*. **407** (2007) 373–381.

**75** (2009) 265–271.

*J*. **320** (Pt 2) (1996) 345–57.

(2004) 1027–32.

**78** (2004) 435–42.

(2004) 958–9.

96 Vitamin K2 - Vital for Health and Wellbeing

[16] Zhou C, Verma S, Blumberg B. The steroid and xenobiotic receptor (SXR), beyond xeno-

[17] Montminy M, and Koo SH. PGC-1 promotes insulin resistance in liver through PPARalpha-dependent induction of TRB-3. Diabetes: outfoxing insulin resistance? *Nature*. **432**

[18] Kodama S, Koike C, Negishi M. and Yamamoto Y. Nuclear receptors CAR and PXR cross talk with FOXO1 to regulate genes that encode drug-metabolizing and gluconeogenic

[19] Miao J, Fang S, Bae Y. and Kemper JK. Functional inhibitory cross-talk between constitutive androstane receptor and hepatic nuclear factor-4 in hepatic lipid/glucose metabolism is mediated by competition for binding to the DR1 motif and to the common

[20] Eaton S, Bartlett K. and Pourfarzam M. Mammalian mitochondrial β-oxidation. *Biochem* 

[21] Wolfrum C, Asilmaz E, Luca E, Friedman JM. and Stoffel M. Foxa2 regulates lipid metabolism and ketogenesis in the liver during fasting and in diabetes. *Nature*. **432**

[22] Kiyosawa N, Tanaka K, Hirao J, Ito K, Niino N, Sakuma K, Kanbori M, Yamoto T, Manabe S. and Matsunuma N. Molecular mechanism investigation of phenobarbitalinduced serum cholesterol elevation in rat livers by microarray analysis. *Arch. Toxicol*.

[23] Bhalla S, Ozalp C, Fang S, et al. Ligand-activated pregnane X receptor interferes with HNF-4 signaling by targeting a common coactivator PGC-1a. Functional implications in hepatic cholesterol and glucose metabolism. *J. Biol. Chem*. **279** (2004) 45139–45147.

[24] Kodama S, Koike C, Negishi M, Yamamoto Y. Nuclear receptors CAR and PXR cross talk with FOXO1 to regulate genes that encode drug-metabolizing and gluconeogenic

[25] Kodama S, Moore R, Yamamoto Y, Negishi M. Human nuclear pregnane X receptor cross-talk with CREB to repress cAMP activation of the glucose-6-phosphatase gene.

[26] Konno Y, Kodama S, Moore R, et al. Nuclear xenobiotic receptor pregnane X receptor locks corepressor silencing mediator for retinoid and thyroid hormone receptors (SMRT) onto the CYP24A1 promoter to attenuate vitamin D3 activation. *Mol. Pharmacol*.

[27] Francis GA, Fayard E, Picard F, and Auwerx J. Nuclear Receptors and the Control of

coactivators, GRIP-1 and PGC-1alpha. *J. Biol. Chem*. **281** (2006) 14537–46.


[44] Hegardt FG. Mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase: A control enzyme in ketogenesis. *Biochem. J*. **338** (1999) 569–582.

**Section 3**

**The Impact of Vitamnin K2 on Bones and Teeth**


**The Impact of Vitamnin K2 on Bones and Teeth**

[44] Hegardt FG. Mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase: A control

[45] Flowers MT, Ntambi JM. Role of stearoyl-coenzyme A desaturase in regulating lipid

[46] Wolfrum C, Asilmaz E, Luca E, et al. Foxa2 regulates lipid metabolism and ketogenesis

[47] Weickert MO, Pfeiffer AF. Signalling mechanisms linking hepatic glucose and lipid

[48] Zhou J, Zhai Y, Mu Y, et al. A novel pregnane X receptormediated and sterol regulatory element-binding protein-independent lipogenic pathway. *J. Biol. Chem*. **281** (2006)

[49] Slatter JG, Templeton IE, Castle JC, Kulkarni A, Rushmore TH, Richards K, He Y, Dai X, Cheng OJ, Caguyang M, Ulrich RG. Compendium of gene expression profiles comprising a baseline model of the human liver drug metabolism transcriptome. Xenobiotica.

in the liver during fasting and in diabetes. *Nature*. **432** (2004) 1027–1032.

enzyme in ketogenesis. *Biochem. J*. **338** (1999) 569–582.

metabolism. *Curr. Opin. Lipidol*. **19** (2008) 248–256.

metabolism. *Diabetologia*. **49** (2006) 1732–1741.

15013–15020.

98 Vitamin K2 - Vital for Health and Wellbeing

**36**(10-11) (2006) 938–962.

**Chapter 6**

**Provisional chapter**

**Vitamin K2 and Bone Health**

Niels Erik Frandsen and Jan Oxholm Gordeladze

mass and osteoporosis as well as other bone diseases.

During the last 20 years, the main clinical effects of vitamin K2 on bone homeostasis have been investigated in both indirect and direct vitamin K treatment regimens. This chapter is mainly based on randomized clinical trials (RCT) lasting for more than 1 year. As for vitamin K1 (phylloquinone, indirect treatment) and vitamin K2 (menaquinone MK‐4 and MK‐7 direct treatment), respectively, the clinical trials have consistently shown decreased fracture rate incidents, however, mainly in Asian populations. In 2013, a major breakthrough was observed by Knapen et al. in the Netherlands, where menaquinone MK‐7 supplementation of 180 μg/day for 3 years to healthy postmeno‐ pausal women significantly decreased the age‐related decline in BMC (bone mineral contents) and BMD (bone mineral density) at the lumbar spine and femoral neck, but not at the total hip, as compared to placebo. Thus, MK‐7 supplementation has shown a significant "double"‐positive action through (1) increased bone building and (2) decreased bone resorption. We look forward to seeing the clinical effects on low bone

**Keywords:** bone health, RCT trials, vitamin K1, vitamin K2 (MK‐4, menatetrenone),

Vitamin K2 (menaquinone‐4, MK‐4, or menatetrenone) is a very important vitamin K species serving special functions in several extrahepatic organs, like bone tissue, heart, blood vessels, kidneys, brain, and cartilage. MK‐4 is a member of a sub‐family with eliciting the same cellular reactions, but with different effects. MK‐4 is deemed necessary for γ‐carboxylation of proteins, and activation of the vitamin K‐dependent proteins, i.e., Osteocalcin (bone‐Gla‐protein), matrix‐ Gla proteins (MGPs), Periostin, as well as protein S. Without these activated proteins, the body

and reproduction in any medium, provided the original work is properly cited.

© 2017 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution,

© 2017 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Niels Erik Frandsen and Jan Oxholm Gordeladze

Additional information is available at the end of the chapter

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/64876

menaquinone‐7 (MK‐7)

**1. Introduction**

**Abstract**

#### **Chapter 6 Provisional chapter**
