**Vitamin K, SXR, and GGCX**

Kotaro Azuma and Satoshi Inoue Kotaro Azuma and Satoshi Inoue

Additional information is available at the end of the chapter Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/63983

#### **Abstract**

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Heart J. 2016 Apr 20. pii: ehw146. [Epub ahead of print].

10.1016/j.bbagrm.2016.04.002. Epub 2016 Apr 11.

eCollection 2016.

20 Vitamin K2 - Vital for Health and Wellbeing

Vitamin K was discovered in 1929 as a substance essential for blood coagulation and had been clinically utilized before the precise mechanism of action became aware in 1970s. The function as a cofactor of γ-glutamyl carboxylase (GGCX) was the mechanism firstly discovered with the identification of several substrate proteins including blood coagulation factors and osteocalcin. Recently, we and others have shown that vitamin K has other modes of function, such as ligand of nuclear receptor SXR (steroid and xenobiotic receptor) and its murine ortholog PXR (pregnane X receptor) and modulator of protein kinase A (PKA) activity. Besides its importance in blood coagulation, involvement of vitamin K has been shown in two major aging-related diseases, osteoporosis and osteoarthritis. Based on clinical and epidemiological studies, vitamin K is shown to have protective roles for both of them. Interestingly, clinical studies concerning single nucleotide polymorphisms (SNPs) of GGCX and γ-carboxylated status of osteocalcin suggested relationship between GGCX activity and bone-protective effect, while recent findings from basic research indicated that vitamin K functions mediated by SXR/PXR as well as GGCX are important in the bone metabolism. We also suggested that cartilage-protective effect is mediated by SXR/PXR signaling by animal experiments using *Pxr* knockout mice.

**Keywords:** γ-glutamyl carboxylase (GGCX), steroid and xenobiotic receptor (SXR), pregnane X receptor (PXR), protein kinase A (PKA), osteocalcin, osteoporosis, osteoarthritis

#### **1. Introduction**

In 1929, a Danish biochemist, Dr. Henrik Dam predicted a fat-soluble diet substance which is essential for blood coagulation. The substance was referred as "Koagulationsvitamin" in

© 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. © 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.

German; thus it is called vitamin K in English named after the initial letter of its German word. He shared the Nobel Prize in Physiology or Medicine in 1943 with an American biochemist Dr. Edward A. Doisy who later identified the structure of vitamin K. During the 1970s, the mechanism of vitamin K began to be revealed with the discovery, namely, vitamin K was necessary for γ-carboxylation of some coagulation factors which is catalyzed by an enzyme called γ-glutamyl carboxylase (GGCX) [1, 2]. Interestingly, warfarin, which inhibits vitamin K function, was in medical use since 1954, and vitamin K administration to newborn babies for preventing intracranial hemorrhage started in many countries in the 1960s before the enzymatic mechanisms of vitamin K function had been clarified.

Recently, epidemiological and clinical studies suggested that vitamin K is related to various physiological and pathological processes besides coagulation. Based on these studies, vitamin K was approved to be used as a drug preventing osteoporotic fracture in several Asian countries. Moreover, for these two decades, another mode of vitamin K action has been elucidated. We discovered vitamin K functions as a ligand for a nuclear receptor, SXR (steroid and xenobiotic receptor), and its murine ortholog, PXR (pregnane X receptor) [3], which have physiological or pathological significance. Summing up, vitamin K plays important roles in wide variety of biological process in various modes of actions.

In this chapter we are going to introduce novel mechanism of vitamin K action mediated by SXR/PXR as well as recent findings concerning classical vitamin K action mediated by GGCX. Then we would like to discuss the functions of vitamin K in some aging-related diseases based on recent discoveries.
