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Title: Atorvastatin decreases renal menaquinone-4 formation in C57BL/6 male mice

Author
item HARSHMAN, STEPHANIE - Massachusetts General Hospital
item SHEA, KYLA - Jean Mayer Human Nutrition Research Center On Aging At Tufts University
item FU, XUEYAN - Jean Mayer Human Nutrition Research Center On Aging At Tufts University
item Grusak, Michael
item SMITH, DONALD - Jean Mayer Human Nutrition Research Center On Aging At Tufts University
item LAMON-FAVA, STEFANIA - Jean Mayer Human Nutrition Research Center On Aging At Tufts University
item KULIOPULOS, ATHAN - Tufts University
item GREENBERG, ANDREW - Jean Mayer Human Nutrition Research Center On Aging At Tufts University
item 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: 10/25/2018
Publication Date: 2/8/2019
Citation: Harshman, S., Shea, K., Fu, X., Grusak, M.A., Smith, D.E., Lamon-Fava, S., Kuliopulos, A., Greenberg, A., Booth, S.L. 2019. Atorvastatin decreases renal menaquinone-4 formation in C57BL/6 male mice. Journal of Nutrition. 149(3):416-421. https://doi.org/10.1093/jn/nxy290.
DOI: https://doi.org/10.1093/jn/nxy290

Interpretive Summary: Menaquinone-4 is a vitamin K metabolite that is converted from phylloquinone, the primary dietary form of vitamin K. Because this conversion involves cholesterol metabolites, it may be blocked by statin drugs because statins block cholesterol production. To test this, we randomly assigned young and old male mice to a normal diet or a diet that contained statins for 8 weeks. For the last week of the study all mice were fed collard greens, which are rich in phylloquinone. The mice given statins had less menaquinone-4 in their kidneys compared to mice not given statins. However, the menaquinone-4 in the liver, brain, and intestine did not differ between the mice given statins and mice not given statins. The results were similar in the young and old mice. These findings suggest cholesterol metabolism is involved in the conversion of phylloquinone to menaquinone-4 in the kidney. There is growing evidence that low vitamin K is implicated in kidney disease, and patients with kidney disease are commonly treated with statins to lower their cholesterol. Therefore, the unique role of menaquinone-4 and its conversion from phylloquinone in the kidney warrants further study.

Technical Abstract: 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 MK4 is involved kidney function. However, this has yet to be demonstrated in vivo. Objective: The purpose of this study was to determine the effect of atorvastatin treatment on MK4 formation in young and old male mice. Methods: Four month (n=32) and 20-month old (n=32) C57BL6 male mice were randomly assigned to either a diet containing 300mg atorvastatin/kg with 3mg phylloquinone/kg or a control diet containing 3mg phylloquinone/kg for 8 weeks. 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 HPLC-MS. HMG-CoA reductase gene expression was quantified by reverse transcriptase-PCR. Tissue MK4 and phylloquinone concentrations were compared between atorvastatin treatment groups using general linear models. Results: Mice given atorvastatin had lower total MK4 and deuterium-labeled MK4 kidney concentrations compared to mice not given atorvastatin (P = 0.02 and 0.04, respectively). In atorvastatin-treated mice, the kidney total MK4 concentration was 41% lower (P < 0.05), and percent deuterium-labeled MK4 was 42% lower compared to mice not given atorvastatin (p=0.008). 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.