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Article

A Hypomethylating Ketogenic Diet in Apolipoprotein E-Deficient Mice: A Pilot Study on Vascular Effects and Specific Epigenetic Changes

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Department of Nutritional Sciences, The Pennsylvania State University, University Park, PA 16802, USA
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Faculty of Pharmacy, Universidade de Lisboa, 1649-003 Lisbon, Portugal
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Research Institute for Medicines (iMed.ULisboa), Universidade de Lisboa, 1649-003 Lisbon, Portugal
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The Huck Institutes of the Life Sciences, The Pennsylvania State University, University Park, PA 16802, USA
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Medical Center Rotterdam, Department of Clinical Chemistry, Erasmus MC University, 3015 GD Rotterdam, The Netherlands
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Jean Mayer USDA Human Nutrition Research Center on Aging, Cardiovascular Nutrition Laboratory, Tufts University, Boston, MA 02111, USA
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Biomedical Engineering, The Pennsylvania State University, University Park, PA 16802, USA
*
Author to whom correspondence should be addressed.
Academic Editors: Dina Bellizzi and Silvia Savastano
Nutrients 2021, 13(10), 3576; https://doi.org/10.3390/nu13103576
Received: 2 September 2021 / Revised: 27 September 2021 / Accepted: 2 October 2021 / Published: 13 October 2021
(This article belongs to the Special Issue Nutrition and Atherosclerosis: From Bench to Bedside)
Hyperhomocysteneinemia (HHcy) is common in the general population and is a risk factor for atherosclerosis by mechanisms that are still elusive. A hypomethylated status of epigenetically relevant targets may contribute to the vascular toxicity associated with HHcy. Ketogenic diets (KD) are diets with a severely restricted amount of carbohydrates that are being widely used, mainly for weight-loss purposes. However, studies associating nutritional ketosis and HHcy are lacking. This pilot study investigates the effects of mild HHcy induced by nutritional manipulation of the methionine metabolism in the absence of dietary carbohydrates on disease progression and specific epigenetic changes in the apolipoprotein-E deficient (apoE–/–) mouse model. ApoE–/– mice were either fed a KD, a diet with the same macronutrient composition but low in methyl donors (low methyl KD, LMKD), or control diet. After 4, 8 or 12 weeks plasma was collected for the quantification of: (1) nutritional ketosis, (i.e., the ketone body beta-hydroxybutyrate using a colorimetric assay); (2) homocysteine by HPLC; (3) the methylating potential S-adenosylmethionine to S-adenosylhomocysteine ratio (AdoHcy/AdoMet) by LC-MS/MS; and (4) the inflammatory cytokine monocyte chemoattractant protein 1 (MCP1) by ELISA. After 12 weeks, aortas were collected to assess: (1) the vascular AdoHcy/AdoMet ratio; (2) the volume of atherosclerotic lesions by high-field magnetic resonance imaging (14T-MRI); and (3) the content of specific epigenetic tags (H3K27me3 and H3K27ac) by immunofluorescence. The results confirmed the presence of nutritional ketosis in KD and LMKD mice but not in the control mice. As expected, mild HHcy was only detected in the LMKD-fed mice. Significantly decreased MCP1 plasma levels and plaque burden were observed in control mice versus the other two groups, together with an increased content of one of the investigated epigenetic tags (H3K27me3) but not of the other (H3K27ac). Moreover, we are unable to detect any significant differences at the p < 0.05 level for MCP1 plasma levels, vascular AdoMet:AdoHcy ratio levels, plaque burden, and specific epigenetic content between the latter two groups. Nevertheless, the systemic methylating index was significantly decreased in LMKD mice versus the other two groups, reinforcing the possibility that the levels of accumulated homocysteine were insufficient to affect vascular transmethylation reactions. Further studies addressing nutritional ketosis in the presence of mild HHcy should use a higher number of animals and are warranted to confirm these preliminary observations. View Full-Text
Keywords: endothelial dysfunction; 14T-MRI; H3K27me3; H3K27ac; histone methylation; histone acetylation; mild hyperhomocysteinemia; homocysteine and vascular disease endothelial dysfunction; 14T-MRI; H3K27me3; H3K27ac; histone methylation; histone acetylation; mild hyperhomocysteinemia; homocysteine and vascular disease
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MDPI and ACS Style

Castro, R.; Whalen, C.A.; Gullette, S.; Mattie, F.J.; Florindo, C.; Heil, S.G.; Huang, N.K.; Neuberger, T.; Ross, A.C. A Hypomethylating Ketogenic Diet in Apolipoprotein E-Deficient Mice: A Pilot Study on Vascular Effects and Specific Epigenetic Changes. Nutrients 2021, 13, 3576. https://doi.org/10.3390/nu13103576

AMA Style

Castro R, Whalen CA, Gullette S, Mattie FJ, Florindo C, Heil SG, Huang NK, Neuberger T, Ross AC. A Hypomethylating Ketogenic Diet in Apolipoprotein E-Deficient Mice: A Pilot Study on Vascular Effects and Specific Epigenetic Changes. Nutrients. 2021; 13(10):3576. https://doi.org/10.3390/nu13103576

Chicago/Turabian Style

Castro, Rita, Courtney A. Whalen, Sean Gullette, Floyd J. Mattie, Cristina Florindo, Sandra G. Heil, Neil K. Huang, Thomas Neuberger, and A. C. Ross. 2021. "A Hypomethylating Ketogenic Diet in Apolipoprotein E-Deficient Mice: A Pilot Study on Vascular Effects and Specific Epigenetic Changes" Nutrients 13, no. 10: 3576. https://doi.org/10.3390/nu13103576

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