Tissue Concentrations of Vitamin K and Expression of Key Enzymes of Vitamin K Metabolism Are Influenced by Sex and Diet but Not Housing in C57Bl6 Mice

Harshman, Stephanie; Fu, Xueyan; Karl, J. Philip; Barger, Kathryn; Lamon‐Fava, Stefania; Kuliopulos, Athan; Greenberg, Andrew S.; Smith, Donald E.; Shen, Xiaohua; Booth, Sarah L.

doi:10.3945/jn.116.233130

Cited by 22 publications

(21 citation statements)

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“…Vitamin K (VK) is an essential micronutrient that vertebrates do not synthesize, thus they depend on dietary sources to obtain the required daily amounts. Nowadays, VK is known to be required for blood coagulation [49,50], skeletal tissue [21] and redox [23,51] homeostasis, sphingolipid [52] and glucose metabolism [53], neural development and cognitive capacities [52,[54][55][56], pathological calcification and inflammation [57][58][59], angiogenesis [60], and reproduction [61][62][63]. Studies in fish also suggest that VK is required for blood coagulation [16,64], skeletal development and skeletal tissues homeostasis [15,17,18], redox homeostasis [18], sphingolipid metabolism [14], brain development and cognitive capacities [19], pathological calcification and inflammation [16], and reproduction [14,16,65], reinforcing the idea of a well conserved function of VK throughout vertebrate evolution [26,66].…”

Section: Discussionmentioning

confidence: 99%

New Insights on Vitamin K Metabolism in Senegalese sole (Solea senegalensis) Based on Ontogenetic and Tissue-Specific Vitamin K Epoxide Reductase Molecular Data

Beato

Marques

Laizé

et al. 2020

IJMS

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Vitamin K (VK) is a key nutrient for several biological processes (e.g., blood clotting and bone metabolism). To fulfill VK nutritional requirements, VK action as an activator of pregnane X receptor (Pxr) signaling pathway, and as a co-factor of γ-glutamyl carboxylase enzyme, should be considered. In this regard, VK recycling through vitamin K epoxide reductases (Vkors) is essential and should be better understood. Here, the expression patterns of vitamin K epoxide reductase complex subunit 1 (vkorc1) and vkorc1 like 1 (vkorc1l1) were determined during the larval ontogeny of Senegalese sole (Solea senegalensis), and in early juveniles cultured under different physiological conditions. Full-length transcripts for ssvkorc1 and ssvkorc1l1 were determined and peptide sequences were found to be evolutionarily conserved. During larval development, expression of ssvkorc1 showed a slight increase during absence or low feed intake. Expression of ssvkorc1l1 continuously decreased until 24 h post-fertilization, and remained constant afterwards. Both ssvkors were ubiquitously expressed in adult tissues, and highest expression was found in liver for ssvkorc1, and ovary and brain for ssvkorc1l1. Expression of ssvkorc1 and ssvkorc1l1 was differentially regulated under physiological conditions related to fasting and re-feeding, but also under VK dietary supplementation and induced deficiency. The present work provides new and basic molecular clues evidencing how VK metabolism in marine fish is sensitive to nutritional and environmental conditions.

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Section: Discussionmentioning

confidence: 99%

New Insights on Vitamin K Metabolism in Senegalese sole (Solea senegalensis) Based on Ontogenetic and Tissue-Specific Vitamin K Epoxide Reductase Molecular Data

Beato

Marques

Laizé

et al. 2020

IJMS

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“…Because we limited our study to males, generalizability to females is uncertain. Sex-specific differences in mice have been identified previously (13). Because this was the first study to evaluate the effect of statin treatment on vitamin K metabolism in vivo, we selected genes known to be involved in cholesterol metabolism.…”

Section: Discussionmentioning

confidence: 99%

Atorvastatin Decreases Renal Menaquinone-4 Formation in C57BL/6 Male Mice

Harshman

Shea

et al. 2019

The Journal of Nutrition

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Background Menaquinone-4 (MK4), a vitamin K metabolite, is converted from phylloquinone through a process that requires intermediates of endogenous cholesterol production. Recent evidence suggests that MK4 is involved in kidney function. Objective The purpose of this study was to determine the effect of atorvastatin treatment on MK4 formation in young and old male mice. Methods C57BL/6 male mice (4-mo-old and 20-mo-old) were randomly assigned to either a diet containing 300 mg atorvastatin/kg with 3 mg phylloquinone/kg or a control diet containing 3 mg phylloquinone/kg for 8 wk. During week 8, all mice received deuterium-labeled phylloquinone in the diet. Labeled and unlabeled phylloquinone and MK4 in liver, kidney, brain, and intestine were measured by atmospheric pressure chemical ionization LC/MS. 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase gene expression was quantified by reverse transcriptase-PCR. Tissue MK4 and phylloquinone concentrations were compared between atorvastatin treatment groups with use of general linear models. Results There was no age-treatment interaction on MK4 tissue concentrations. In atorvastatin-treated mice, total MK4 and percentage of deuterium-labeled MK4 in kidney were both approximately 45% lower compared to values in mice not given atorvastatin (all P < 0.05). MK4 concentrations did not differ between groups in any other tissue measured. Conclusion In male mice, atorvastatin reduced endogenous MK4 formation in the kidney, but not other organs. These observations are consistent with our hypothesis that cholesterol metabolism is involved in the generation of MK4. Further research is needed to understand potential regulatory mechanisms and the unique functions of MK4 in the kidney.

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“…Important to consider in the interpretation of the above data are notable sex and age differences in tissue vitamin K levels that could have significant implications when supplementing patients with CKD [ 23 , 24 ]. Harshman et al characterized the sex differences in the vitamin K metabolome in C57BI6 mice exposed to vitamin K-sufficient and -deficient diets [ 23 ]. The metabolome was characterized in the liver, kidney, the brain, mesenteric adipose tissue, and the pancreas.…”

Section: Circulating and Tissue Measures Of Vitamin K 1 mentioning

confidence: 99%

“…The assay used quantified the tissues’ abilities to convert the vitamin K1 epoxide to the corresponding K1 quinione. While both studies above used male rats, it is important to note that sex-specific differences have been demonstrated in Vkorc1 expression in the liver and pancreas in healthy rats [ 23 ]. In addition, in the low dietary vitamin K 1 condition of this study, there was a suppression and elevation of Vkorc1 in the liver and adipose tissue, respectively.…”

Section: The Vitamin K Cycle In Ckdmentioning

confidence: 99%

“…The expression of GGCX is regulated, in part, as a result of sex and dietary restriction. Notably, a reduced expression as a result of dietary K restriction in the liver and kidney was more apparent in male rats, and a substantial increase in brain expression as a result of dietary restriction was more apparent in female rats [ 23 ]. Whether this confers an alteration in protein expression or activity has yet to be determined.…”

Section: The Vitamin K Cycle In Ckdmentioning

confidence: 99%

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The Vitamin K Metabolome in Chronic Kidney Disease

2018

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The purpose of this review is to summarize the research to date on the impact of chronic kidney disease (CKD) on the vitamin K metabolome. Vitamin K-dependent proteins contribute to cardiovascular disease (CVD) prevention via the prevention of ectopic mineralization. Sub-clinical vitamin K deficiency is common in CKD patients, and evidence suggests that it may contribute to the CVD burden in this population. Research from animal models suggests that CKD alters tissue measures of the two predominant forms of vitamin K: KI and MK-4. The expression and/or activity of enzymes that regulate the recycling of vitamin K and the carboxylation of vitamin K-dependent proteins also appear to be altered in CKD. Evidence suggests that statins, a common pharmaceutical prescribed to CKD patients to prevent cardiovascular events, may impact the metabolism of vitamin K and therefore contribute to its relative inefficiency at preventing CVD in this population as kidney disease progresses. Human research on the tissue vitamin K metabolome in CKD patients is lacking.

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Tissue Concentrations of Vitamin K and Expression of Key Enzymes of Vitamin K Metabolism Are Influenced by Sex and Diet but Not Housing in C57Bl6 Mice

Cited by 22 publications

References 50 publications

New Insights on Vitamin K Metabolism in Senegalese sole (Solea senegalensis) Based on Ontogenetic and Tissue-Specific Vitamin K Epoxide Reductase Molecular Data

New Insights on Vitamin K Metabolism in Senegalese sole (Solea senegalensis) Based on Ontogenetic and Tissue-Specific Vitamin K Epoxide Reductase Molecular Data

Atorvastatin Decreases Renal Menaquinone-4 Formation in C57BL/6 Male Mice

The Vitamin K Metabolome in Chronic Kidney Disease

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