A High-Fat Diet Induces Epigenetic 1-Carbon Metabolism, Homocystinuria, and Renal-Dependent HFpEF

Overview

Journal Nutrients

Date 2025 Jan 25

PMID 39861346

Authors

Suresh C Tyagi

Affiliations

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Abstract

Background/objectives: Chronic 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/results: One 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).

Conclusions: We 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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