A hypomethylating ketogenic diet in apolipoprotein e-deficient mice: a pilot study on vascular effects and specific epigenetic changes

10Citations
Citations of this article
31Readers
Mendeley users who have this article in their library.

Abstract

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.

References Powered by Scopus

Fiji: An open-source platform for biological-image analysis

43315Citations
N/AReaders
Get full text

Absence of monocyte chemoattractant protein-1 reduces atherosclerosis in low density lipoprotein receptor-deficient mice

1418Citations
N/AReaders
Get full text

Suppression of oxidative stress by β-hydroxybutyrate, an endogenous histone deacetylase inhibitor

1313Citations
N/AReaders
Get full text

Cited by Powered by Scopus

Exercise Ameliorates Atherosclerosis via Up-Regulating Serum β-Hydroxybutyrate Levels

16Citations
N/AReaders
Get full text

The Effect of Nutritional Ketosis on Aquaporin Expression in Apolipoprotein E-Deficient Mice: Potential Implications for Energy Homeostasis

6Citations
N/AReaders
Get full text

High-field magnetic resonance microscopy of aortic plaques in a mouse model of atherosclerosis

5Citations
N/AReaders
Get full text

Register to see more suggestions

Mendeley helps you to discover research relevant for your work.

Already have an account?

Cite

CITATION STYLE

APA

Castro, R., Whalen, C. A., Gullette, S., Mattie, F. J., Florindo, C., Heil, S. G., … Ross, A. C. (2021). A hypomethylating ketogenic diet in apolipoprotein e-deficient mice: a pilot study on vascular effects and specific epigenetic changes. Nutrients, 13(10). https://doi.org/10.3390/nu13103576

Readers over time

‘21‘22‘23‘24‘2505101520

Readers' Seniority

Tooltip

PhD / Post grad / Masters / Doc 2

67%

Researcher 1

33%

Readers' Discipline

Tooltip

Medicine and Dentistry 2

33%

Biochemistry, Genetics and Molecular Bi... 2

33%

Materials Science 1

17%

Engineering 1

17%

Save time finding and organizing research with Mendeley

Sign up for free
0