**4. The effect of vitamin K2 on other genes related to metabolic processes in the cell**

by funneling long-chain fatty acids into mitochondria [43], and the mitochondrial enzyme

Additionally, the stimulation of SXR by PCN has been demonstrated to enhance the mRNA steady state level of stearoyl-CoA desaturase 1 (Scd1) in hepatic tissue of starved wild-type experimental animals. SCD1, which serves as a key enzyme in hepatic lipogenesis, facilitates the rate-limiting step in the synthesis of unsaturated fatty acids [45]. The plasma concentrations of 3-OH-butylate were decreased, while the hepatic level of triglyceride (TG) was increased by the PCN treatment in wild-type mice during assay conditions. However, neither TG nor cholesterol levels in the blood were altered in those animals, despite the fact that there was a significant rise in TG accumulated in their liver. Hence, as a means of survival during fasting, SXR is thought to slow down hepatic lipid turnover by repressing β-oxidation and ketogenesis, while stimulating the transcription of lipogenic enzymes, in much the same way

The Akt-regulated forkhead transcription factor FoxA2 which serves as a facilitator of insulin-dependent modulation of β-oxidation and ketogenesis, enhances expression of both the CPT1a and HMGCS2 gene, respectively [21, 46]. It is well known that Insulin activates the PI3K/Akt signaling pathway to phosphorylate FoxA2, in order to translocate it from nucleus to cytosol, thereby downregulating both the genes. And, it has been asserted that a direct interaction between SXR and FoxA2 serves as the mechanism, by which SXR represses the

A plethora of transcription factors and coregulators have been asserted to serve as modulators of hepatic lipid metabolism, e.g., the peroxisome proliferator-activated receptors (PPARs), the liver X receptor α (LXRα), as well as the sterol regulatory element-binding proteins (SREBPs) [47]. The expression of SREBP1c, which is construed as the dominant regulator of hepatic lipogenesis, is under the control of LXRα, and mediates the insulin- and fatty acids-dependent responses of lipogenic genes such as fatty acid synthase (FAS), acetyl-CoA carboxylase 1 (ACC1), stearoyl-CoA-desaturase-1 (SCD1), and fatty acid elongase (FAE). SXR is believed to upregulate lipogenesis in the liver, independently of SREBP1c action, and it is not deemed to be associated with the steady state expression levels of both the Fas and Acc1 genes. Among the cluster of lipogenic genes, Cd36 (cluster of differentiation 36) is deemed to be serve as a direct target of SXR in the liver. And, upon stimulation by ligands, the receptor is believed to become recruited to a DR3-type SXR response element within its promoter region of the liver of experimental animals [48]. Furthermore, SXR has been asserted to serve as a link, facilitating the upregulation of the Pparγ-gene, which functions as a strong regulator of lipid-synthesizing enzymes [48]. Such a cross-talk involving nuclear receptors should confer a significant impact on the body's lipid homeostasis. Our data are in line with the published literature, however, it should be asserted that SXR probably affects a larger spectrum of FoxO and FoxA species than those presented in this review. In this way, one might speculate that SXR is able to recruit a "moving" representation of these transcription factors simultaneously, and that the net effect on various cell phenotypes depends on: (1) the distribution of FoxOs and FoxAs at any time within the cell or tissue, as well as (2) the epigenetic machinery or "make up" at any time

HMGCS2 facilitates the initial reaction of ketogenesis [44].

transcription of CPT1a and HMGCS2 in the liver [32].

as induced by insulin.

92 Vitamin K2 - Vital for Health and Wellbeing

within the same cells or tissues.

In 2009, Slatter [49] and coworkers published a paper, featuring oligonucleotide microarrays with the intention to reveal the heterogeneity of drug metabolism associated gene expression in liver tissue from healthy humans. Their intention was to define clusters of so-called "absorption, distribution, metabolism, and excretion" = ADME genes to define subgroups of coregulated genes. When analyzing the gene sets, they discovered distinct patterns of "parallel" gene expressions featuring gene "clusters", which proved to be modulated by the nuclear receptor SXR. So called "fold range metrics and frequency distributions" were applied in order to reveal the variability of solitary PKDM genes. The most variable gene entities chiefly correlated to: (1) drug metabolism, (2) intermediary metabolism, (3) inflammation, and (4) cell cycle control. Unique expression patterns of these genes allowed for a further correlation with a parallel expression of a plethora of other genes. Of major interest was the identification of SXR responsive genes.

A comprehensive list of these genes can be found in the article, however, quite a few of which are related to metabolic processes in the cell. The genes are the following (in alphabetical order): CLOCK, DUSP7, GCDH, IGFBP2, MAP2K2, NUCB2, OGT, PFKB1, PTPN11, and SLC16A2. By "looking up" current descriptions of the genes in "Gene-Cards", the following features of these SXR-sensitive genes were obtained (of which parts of their description is cited as presented):


#### 94 Vitamin K2 - Vital for Health and Wellbeing


[3] Lowell BB, Susulic VS, Hamann A, Lawitts JA, Himms-Hagen J, Boyer BB, Kozak LP, Flier JS. Development of obesity in transgenic mice after genetic ablation of brown adi-

The Impact of Vitamin K2 on Energy Metabolism

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

95

[4] Seale P, Bjork B, Yang W, Kajimura S, Chin S, Kuang S, Scime A, Devarakonda S, Conroe HM, Erdjument-Bromage H, et al. PRDM16 controls a brown fat/skeletal muscle switch.

[5] Wu J, Bostrom P, Sparks LM, Ye L, Choi JH, Giang AH, Khandekar M, Virtanen KA, Nuutila P, Schaart G, et al. Beige adipocytes are a distinct type of thermogenic fat cell in

[6] Fisher FM, Kleiner S, Douris N, Fox EC, Mepani RJ, Verdeguer F, Wu J, Kharitonenkov A, Flier JS, Maratos-Flier E, et al. FGF21 regulates PGC-1α and browning of white adi-

[7] Bostrom P, Wu J, Jedrychowski MP, Korde A, Ye L, Lo JC, Rasbach KA, Bostrom EA, Choi JH, Long JZ, et al. A PGC1-α-dependent myokine that drives brown-fat-like devel-

[8] Cederberg A, Gronning LM, Ahren B, Tasken K, Carlsson P, Enerback S. FOXC2 is a winged helix gene that counteracts obesity, hypertriglyceridemia, and diet-induced insulin resis-

[9] Seale P, Conroe HM, Estall J, Kajimura S, Frontini A, Ishibashi J, Cohen P, Cinti S, Spiegelman BM. Prdm16 determines the thermogenic program of subcutaneous white

[10] Ohno H, Shinoda K, Spiegelman BM, Kajimura S. PPARγ agonists induce a white-tobrown fat conversion through stabilization of PRDM16 protein. *Cell Metab*. **15** (2012)

[11] Qiang L, Wang L, Kon N, Zhao W, Lee S, Zhang Y, Rosenbaum M, Zhao Y, Gu W, Farmer SR, et al. Brown remodeling of white adipose tissue by SirT1-dependent deacetylation of

[12] Cohen P, Levy JD, Zhang Y, Frontini A, Kolodin DP, Svensson KJ, Lo JC, Zeng X, Ye L, Khandekar MJ, et al. Ablation of PRDM16 and beige adipose causes metabolic dysfunc-

[13] Lecka-Czernik B, Stechschulte LA. Protein Phosphatase PP5 Controls Bone Mass and the Negative Effects of Rosiglitazone on Bone through Reciprocal Regulation of PPARγ (Peroxisome Proliferator-activated Receptor γ) and RUNX2 (Runt-related Transcription

[14] Aguirre L, Napoli N, Waters D, Qualls C, Villareal DT, Armamento-Villareal R. Increasing adiposity is associated with higher adipokine levels and lower bone mineral density in

tion and a subcutaneous to visceral fat switch. *Cell*. **156** (2014) 304–316.

obese older adults. *Clin. J. Endocrinol. Metab*. **99**(9) (2014) 3290–3297.

pose tissues in adaptive thermogenesis. *Genes Dev*. **26** (2012) 271–281.

opment of white fat and thermogenesis. *Nature*. **481** (2012) 463–468.

adipose tissue in mice. *J. Clin. Invest*. **121** (2011) 96–105.

Factor 2). *Arch*. *Biochem. Biophys*. **561** (2014) 124–129.

pose tissue. *Nature*. **366** (1993) 740–742.

mouse and human. *Cell*. **150** (2012) 366–376.

*Nature*. **454** (2008) 961–967.

tance. *Cell*. **106** (2001) 563–573.

Pparγ. *Cell*. **150** (2012) 620–632.

395–404.
