Histone β-hydroxybutyrylation-mediated Chromatin Remodeling Upregulates β-oxidation of Fatty Acids and Attenuates Metabolic Syndrome

Abstract

Center for Hypertension and Precision Medicine, Department of Physiology and Pharmacology, University of Toledo, Toledo, OH Introduction: Metabolic syndrome (MetS) is a cluster of metabolic dysregulations including high blood pressure (BP), dyslipidemia, central obesity, hyperglycemia, and insulin resistance. Regular exercise is one of the lifestyle modifications known to prevent MetS by the generation of ketone bodies. Precisely how ketone bodies operate to lower MetS is largely unknown. Previously, we demonstrated that the ketone body, β-hydroxybutyrate, is a potent anti-hypertensive metabolite. β-hydroxybutyrate has been recently recognized to epigenetically modify histones by β-hydroxybutyrylation. Using assay for transposase-accessible chromatin with sequencing and chromatin immunoprecipitation assays, we found that histone β-hydroxybutyrylation causes chromatin remodeling and exposes regions for transcription of genes for β-oxidation of fatty acids. Therefore, we hypothesized that β-hydroxybutyrate alleviates MetS via histone β-hydroxybutyrylation-mediated transcriptional upregulation of β-oxidation of fatty acids. To test this hypothesis, we examined the epigenetic effect of increasing systemic β-hydroxybutyrate in a genetic rat model of MetS inbred in our laboratory, the low-capacity runner (LCR/Tol) rats. Methods: Randomly selected two groups of six months old female LCR/Tol rats (n=5/group) were surgically implanted with radiotelemetry transmitters for BP measurement. The control group was given water, whereas the experimental group was given water containing 20% v/v of 1,3-butanediol (1,3-BD), which is a precursor of β-hydroxybutyrate for 10 weeks. Following euthanasia, sera and tissues were harvested. Histones were isolated and subjected to western blotting for quantitation of β-hydroxybutyrylation. Results: Compared to the control group, rats given 1,3-BD had a significantly increased circulating β-hydroxybutyrate (mean 1.98 mM vs 0.71 mM, p<0.05), lower body weight (mean 231.6 gm vs 248.4 gm, p<0.05), lower fasting glucose (mean 79.60 mg/dl vs 100.8 mg/dl, p<0.05) and lower 24-hour average systolic BP (116±2 mmHg vs. 120±2 mmHg, p<0.05). Interestingly, histones isolated from the experimental group with higher circulating β-hydroxybutyrate also displayed a marked increase in β-hydroxybutyrylation (mean 0.82 vs 0.22, p<0.01). Further, the target transcriptional genes of histone β-hydroxybutyrylation, 3-hydroxy-3-methylglutaryl-CoA synthase 2 (Hmgcs2) and cytochrome P450 family 2 subfamily d polypeptide 4 (Cyp2d4) were both significantly upregulated in the experimental group (p<0.01). However, markers of liver injury, alanine transaminase, alkaline phosphatase, aspartate transaminase, and total bile acid levels, were comparable between the two groups, indicating no liver damage. Conclusion: This is the first study to demonstrate that enhanced systemic β-hydroxybutyrate attenuates MetS by histone β-hydroxybutyrylation-mediated chromatin remodeling to upregulate the transcription of Hmgcs2 and Cyp2d4 to promote β-oxidation of fatty acids. Further, our results demonstrate that for individuals with MetS who may be unable to exercise, utilizing 1,3-BD could serve as an alternate source to combat the MetS ameliorating benefits of the ketone body β-hydroxybutyrate. Funding Sources: Authors acknowledge the National Institutes of Health for funding support to Bina Joe (R01HL1430820). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.