Multiple dietary vitamin K forms are converted to tissue menaquinone-4 in mice

Authors: ELLIS, JESSIE - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; FU, XUEYAN - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; KARL, PHILIP - Environmental Laboratory, Us Army Engineer Research And Development Center, Waterways Experiment St; HERNANDEZ, CHRISTOPHER - Cornell University; MASON, JOEL - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; DEBOSE-BOYD, RUSSELL - University Of Texas Southwestern Medical Center; BOOTH, SARAH - Jean Mayer Human Nutrition Research Center On Aging At Tufts University

Submitted to: Journal of Nutrition
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 9/14/2021
Publication Date: 11/9/2021
Citation: Ellis, J.L., Fu, X., Karl, P.J., Hernandez, C.J., Mason, J.B., Debose-Boyd, R.A., Booth, S. 2021. Multiple dietary vitamin K forms are converted to tissue menaquinone-4 in mice. Journal of Nutrition. https://doi.org/10.1093/jn/nxab332.
DOI: https://doi.org/10.1093/jn/nxab332

Interpretive Summary: Vitamin K refers to a family of compounds, including the plant-based phylloquinone and the menaquinones, which are present in animal products and fermented foods. Following intake, dietary phylloquinone is transformed into the metabolite, menaquinone-4 (MK4) in many tissues. Little is known though about the absorption and metabolism of menaquinones that are obtained from the diet. To characterize absorption and metabolism of dietary menaquinones relative to phylloquinone, two studies were conducted. Male and female mice were fed a vitamin K deficient diet or a diet supplemented with different forms and combinations of vitamin K, and their relative tissue contents of vitamin K were compared. Regardless of the vitamin K form fed, all the mice had the same amount of the metabolite, MK4, in most of their tissues. Our demonstration in mice that multiple vitamin K forms are precursors to tissue MK4 expands our knowledge of vitamin K and challenges superiority claims of any particular dietary vitamin K form. Further investigation of the metabolism, regulation, and physiological roles of MK4 are warranted.

Technical Abstract: Background: Vitamin K is a term that comprises a family of structurally related quinones, phylloquinone (PK) and the menaquinones (MKn), that share a common naphthoquinone ring but vary in sidechain length (n) and saturation. Dietary PK is a biosynthetic precursor to tissue menaquinone-4 (MK4), but little is known about the absorption and metabolism of dietary MKn. Objective: To characterize the absorption and metabolism of dietary MKn relative to PK. Methods: In the 4-week diet study, 10-week-old male and female C57BL/6 mice were pair-fed a vitamin K deficient diet (control) or a diet supplemented with 5.0 mu mol/kg total PK, MK4, and/or MK9 (separately and in combination). In the 1-week stable isotope study, 12-week-old mice were pair-fed diets containing 2.2 mu mol/kg PK (unlabeled control), 2H7PK, 13C11MK4, 2H7MK7, or 2H7MK9. Vitamin K tissue content was quantified by HPLC and/or LC-MS, and concentrations were compared by sex and diet group using 2-factor ANOVA. Results: Regardless of the form(s) of vitamin K provided in the diet, tissue MK4 concentrations did not differ across equimolar supplemented groups in the kidney, adipose, reproductive organ, bone, or pancreas in either males or females in the diet study (all P values > 0.05). Isotopic labeling confirmed the naphthoquinone ring of MK4 in tissues originated from the administered dietary PK or MKn. Despite equimolar supplementation, accumulation of the administered dietary form differed across diet groups in small intestinal segments (all P values < 0.002) and the liver (P < 0.001). Female mice had greater total vitamin K than males in every tissue examined (P < 0.05). Conclusions: Dietary PK, MK4, MK7, and MK9 all served as precursors to tissue MK4 in mice. This study expands our understanding of vitamin K metabolism and supports a common conversion mechanism of all dietary vitamin K forms to MK4. Further investigation of the metabolism and physiological roles of MK4 that may be independent of classical vitamin K function is warranted.