ArticleNutrients2025
A High-Fat Diet Induces Epigenetic 1-Carbon Metabolism, Homocystinuria, and Renal-Dependent HFpEF.
Article in Nutrients, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 3 papers.
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Who cites it
3 citing papers in PubMed.
- Genome-Wide DNA Methylation Changes Induced by High-Fat Diet and Methyl Donor Supplementation in Female Lupus Models: An Exploratory Study.Molecular nutrition & food research · 2026Article
- Transsulfuration Pathway Products and HInternational journal of molecular sciences · 2025Review
- Animal Model Screening for Hyperlipidemic ICR Mice.International journal of molecular sciences · 2025Article
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1 author.
Funding
Abstract
BACKGROUND/
objectivesChronic gut dysbiosis due to a high-fat diet (HFD) instigates cardiac remodeling and heart failure with preserved ejection fraction (HFpEF), in particular, kidney/volume-dependent HFpEF. Studies report that although mitochondrial ATP citrate lyase (ACLY) supports cardiac function, it decreases more in human HFpEF than HFrEF. Interestingly, ACLY synthesizes lipids and creates hyperlipidemia. Epigenetically, ACLY acetylates histone. The mechanism(s) are largely unknown. METHODS/
resultsOne hypothesis is that an HFD induces epigenetic folate 1-carbon metabolism (FOCM) and homocystinuria. This abrogates dipping in sleep-time blood pressure and causes hypertension and morning heart attacks. We observed that probiotics/lactobacillus utilize fat/lipids post-biotically, increasing mitochondrial bioenergetics and attenuating HFpEF. We suggest novel and paradigm-shift epigenetic mitochondrial sulfur trans-sulfuration pathways that selectively target HFD-induced HFpEF. Previous studies from our laboratory, using a single-cell analysis, revealed an increase in the transporter (SLC25A) of s-adenosine-methionine (SAM) during elevated levels of homocysteine (Hcy, i.e., homocystinuria, HHcy), a consequence of impaired epigenetic recycling of Hcy back to methionine due to an increase in the FOCM methylation of H3K4, K9, H4K20, and gene writer (DNMT) and decrease in eraser (TET/FTO). Hcy is transported to mitochondria by SLC7A for clearance via sulfur metabolomic trans-sulfuration by 3-mercaptopyruvate sulfur transferase (3MST).
conclusionsWe conclude that gut dysbiosis due to HFD disrupts rhythmic epigenetic memory via FOCM and increases in DNMT1 and creates homocystinuria, leading to a decrease in mitochondrial trans-sulfuration and bioenergetics. The treatment with lactobacillus metabolites fat/lipids post-biotically and bi-directionally produces folic acid and lactone-ketone body that mitigates the HFD-induced mitochondrial remodeling and HFpEF.
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