[Literature Interpretation] Pyruvate metabolic enzyme Dlat limits fatty acid oxidation in HFpEF hearts by inducing mitochondrial protein hyperacetylation.
Release time:
2026-09-20
Foreword
From August 28 to 31 local time, the 2026 European Society of Cardiology Congress (ESC 2026) kicked off in Munich.
At this year’s congress, Professor Li Yan’s team from Tangdu Hospital, Air Force Medical University, successively presented multiple research findings. From the perspectives of metabolite signaling, protein post-translational modifications, epigenetics and RNA regulation, to clinical imaging and interventional therapy evaluation, they reported several new advances in the clinical treatment and pathogenesis of metabolic cardiovascular diseases, shining on the academic stage of ESC 2026.
The paper shared here, “Pyruvate metabolic enzyme Dlat limits fatty acid oxidation in HFpEF hearts by inducing mitochondrial protein hyperacetylation,” was also presented at the congress. Echocardiography in this study was performed using our VINNO small-animal ultrasound system. Please join us as we take a closer look.
Research Highlights:
This study focuses on the mechanistic link between protein hyperacetylation and myocardial metabolic dysfunction in heart failure with preserved ejection fraction (HFpEF), revealing a novel metabolic regulatory axis that drives the development and progression of HFpEF.
The study established an HFpEF mouse model using a high-fat diet combined with L-NAME. It found that myocardial protein hyperacetylation occurred predominantly in mitochondria and was significantly enriched in the fatty acid oxidation (FAO) pathway, accompanied by reduced FAO capacity and abnormal lipid accumulation. Enhancing mitochondrial protein deacetylation restored FAO and improved cardiac function, suggesting that protein acetylation is an important regulatory mechanism underlying metabolic remodeling in HFpEF.
Objective: To characterize the HFpEF phenotype in a 2-hit model and simultaneously reveal the molecular feature of mitochondrial FAO protein hyperacetylation.
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A-C: Doppler echocardiography was used to assess diastolic function indices E/A and E/e’; E/A and E/e’ were significantly elevated in the HFpEF group, confirming diastolic dysfunction.
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D: Treadmill running distance: exercise endurance was reduced in HFpEF mice.
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E: Gross HE staining of the heart; HFpEF hearts were enlarged.
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F: Increased heart weight/tibia length (HW/TL) ratio, suggesting myocardial hypertrophy.
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G-H: WGA staining of cardiomyocyte membranes, with quantification of cardiomyocyte cross-sectional area (CSA): cardiomyocyte hypertrophy in HFpEF.
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I: Masson’s trichrome staining; increased interstitial fibrosis area in HFpEF myocardium.
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J: Western blot analysis of total protein lysine acetylation (LysAc): total myocardial protein acetylation was significantly increased in HFpEF.
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K: Volcano plot of the acetylated proteome: in HFpEF vs. control, 1,070 acetylated peptides were upregulated and 828 were downregulated.
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L: Fold-change distribution of upregulated/downregulated acetylated peptides; 79 peptides had FC > 10 (hyperacetylated).
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M: Pie chart of subcellular localization: most upregulated acetylated proteins were localized to mitochondria.
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N-O: Western blot of separated cytosolic and mitochondrial fractions: mitochondrial protein acetylation was specifically increased, with little change in the cytosol.
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P: KEGG enrichment: hyperacetylated proteins were enriched in energy metabolism pathways such as lipid metabolism, the TCA cycle, and amino acid metabolism.
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Q-R: Bodipy staining for lipid droplets (LDs): the number of lipid droplets in HFpEF cardiomyocytes was significantly increased, indicating lipid accumulation.
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S-T: Oroboros mitochondrial respiration measurements: basal respiration in HFpEF hearts was mildly decreased, and fatty acid oxidation (FAO) respiration was significantly decreased.
Further study identified for the first time that the pyruvate metabolic enzyme Dlat is a key transacetylase mediating mitochondrial protein hyperacetylation in HFpEF myocardium. Mechanistically, Dlat can directly bind to HADHA, the alpha subunit of mitochondrial trifunctional protein, promoting its acetylation at K728 and inhibiting HADHA enzyme activity, thereby leading to impaired FAO, lipid metabolic disorder, and cardiac dysfunction. Dlat knockdown significantly improved the HFpEF phenotype, whereas cardiac-specific overexpression of HADHA or oral biogenic polyamines restored FAO capacity and intervened in an already established HFpEF model.
Objective: To determine whether increasing Dlat only in the myocardium in vivo, without external high-fat/L-NAME stimulation, is sufficient to reproduce the full spectrum of HFpEF features.
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A: Timeline of transgenic mouse experiments: Rosa26^LSL-Dlat × Myh6-Cre; tamoxifen was injected at 4 weeks of age to induce cardiomyocyte-specific Dlat overexpression (Dlat^Tg).
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B: Western blot verification of the efficiency of myocardial Dlat overexpression.
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C: Total protein acetylation: myocardial protein acetylation was increased in Dlat^Tg mice.
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D-E: Western blot of cytosolic/mitochondrial fractions: the increased acetylation occurred mainly in mitochondria.
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F-G: Acetylated proteome: 478 peptides showed upregulated acetylation in Dlat^Tg mouse hearts; more than half were localized to mitochondria.
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H: KEGG enrichment: upregulated acetylated proteins were enriched in oxidative phosphorylation and fatty acid oxidation pathways.
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I-K: Oroboros respiration: basal respiration in Dlat^Tg hearts showed little change, but FAO respiratory capacity was significantly decreased.
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L: Lipid droplet staining: lipid droplet accumulation in Dlat^Tg myocardium.
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M-O: Echocardiography: Dlat^Tg mice developed diastolic dysfunction (abnormal E/A and E/e’), while systolic function EF remained normal, consistent with HFpEF.
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P-U: Histological examination: Dlat^Tg mice exhibited myocardial hypertrophy (increased HW/TL and enlarged cardiomyocyte CSA) and myocardial interstitial fibrosis.
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Objective: Translational exploration: It has been reported that spermidine (SPD) can directly bind to and activate HADHA; to test the therapeutic effect of SPD in an HFpEF mouse model.
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A-B: HADHA enzyme activity assay: HADHA enzyme activity was decreased in HFpEF myocardium; adding SPD to drinking water increased HADHA enzyme activity.
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C-E: Oroboros respiration: SPD treatment restored FAO respiratory capacity in HFpEF hearts.
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F-G: Bodipy lipid droplet staining: SPD reduced lipid droplet accumulation in HFpEF myocardium.
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H-K: Echocardiography: SPD intervention significantly improved diastolic function E/A and E/e’ in HFpEF mice.
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L: Treadmill test: SPD improved exercise endurance in HFpEF mice.
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M-N: HW/TL ratio: SPD alleviated myocardial hypertrophy in HFpEF.
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O-Q: Quantification of WGA and Masson staining: SPD reduced cardiomyocyte cross-sectional area and attenuated interstitial fibrosis.
Research summary:
This study established a novel mechanistic chain of “Dlat-mediated protein acetylation—HADHA inactivation—FAO impairment—HFpEF,” providing a new theoretical basis and potential therapeutic strategies for targeting mitochondrial protein acetylation and fatty acid metabolism in the prevention and treatment of HFpEF.
Publication Information
Authors:
Ying Wang, Dong Guo, Jin’ao Zhu, Xue Yang, Chan Wu, Jing Geng, Qi Liang, Nan Sun, Xiaona Niu, Yue Liu, Yanjie Guo, Pan Chang, Yan Li & Lang Hu
Publisher:
Nature Communications volume 17, Article number: 3929 (2026)
doi: https://doi.org/10.1038/s41467-026-70703-w
Original article link: https://www.nature.com/articles/s41467-026-70703-w
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