Correlation between increased atrial expression of genes related to fatty acid metabolism and autophagy in patients with chronic atrial fibrillation

AbstractAtrial metabolic disturbance contributes to the onset and development of atrial fibrillation (AF). Autophagy plays a role in maintaining the cellular energy balance. We examined whether the altered atrial expression of genes related to fatty acid metabolism is linked to that related to autophagy in chronic AF. Right atrial tissue was obtained during heart surgery from 51 patients with sinus rhythm (SR, n=38) or chronic AF (n=13). Preoperative fasting serum free-fatty-acid levels were significantly higher in the AF patients. The atrial gene expression of fatty acid binding protein 3 (FABP3), which is involved in the cells’ fatty acid uptake and intracellular fatty acid transport, was significantly increased in AF patients compared to SR patients; in the SR patients it was positively correlated with the right atrial diameter and intra-atrial EMD, parameters of structural and electrical atrial remodeling that was evaluated by an echocardiography. In contrast, the two groups’ atrial contents of diacylglycerol (DAG), a toxic fatty acid metabolite, were comparable. Importantly, the atrial gene expression of microtubule-associated protein light chain 3 (LC3) was significantly increased in the AF patients, and autophagy-related genes including LC3 were positively correlated with the atrial expression of FABP3. In conclusion, in chronic AF patients, the atrial expression of FABP3 was upregulated in association with autophagy-related genes without altered atrial DAG content. Our findings may support the hypothesis that dysregulated cardiac fatty acid metabolism contributes to the progression of AF and induction of autophagy has a cardioprotective effect against cardiac lipotoxicity in chronic AF.

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Coordinated multitissue transcriptional and plasma metabonomic profiles following acute caloric restriction in mice

Physiological Genomics ◽

10.1152/physiolgenomics.00084.2006 ◽

2006 ◽

Vol 27 (3) ◽

pp. 187-200 ◽

Cited By ~ 79

Author(s):

Colin Selman ◽

Nicola D. Kerrison ◽

Anisha Cooray ◽

Matthew D. W. Piper ◽

Steven J. Lingard ◽

...

Keyword(s):

Gene Expression ◽

Fatty Acid ◽

Caloric Restriction ◽

Fatty Acid Metabolism ◽

Acid Metabolism ◽

Proton Nuclear Magnetic Resonance ◽

Cellular Transport ◽

Expression Of Genes ◽

Transcriptional Changes

Caloric restriction (CR) increases healthy life span in a range of organisms. The underlying mechanisms are not understood but appear to include changes in gene expression, protein function, and metabolism. Recent studies demonstrate that acute CR alters mortality rates within days in flies. Multitissue transcriptional changes and concomitant metabolic responses to acute CR have not been described. We generated whole genome RNA transcript profiles in liver, skeletal muscle, colon, and hypothalamus and simultaneously measured plasma metabolites using proton nuclear magnetic resonance in mice subjected to acute CR. Liver and muscle showed increased gene expressions associated with fatty acid metabolism and a reduction in those involved in hepatic lipid biosynthesis. Glucogenic amino acids increased in plasma, and gene expression for hepatic gluconeogenesis was enhanced. Increased expression of genes for hormone-mediated signaling and decreased expression of genes involved in protein binding and development occurred in hypothalamus. Cell proliferation genes were decreased and cellular transport genes increased in colon. Acute CR captured many, but not all, hepatic transcriptional changes of long-term CR. Our findings demonstrate a clear transcriptional response across multiple tissues during acute CR, with congruent plasma metabolite changes. Liver and muscle switched gene expression away from energetically expensive biosynthetic processes toward energy conservation and utilization processes, including fatty acid metabolism and gluconeogenesis. Both muscle and colon switched gene expression away from cellular proliferation. Mice undergoing acute CR rapidly adopt many transcriptional and metabolic changes of long-term CR, suggesting that the beneficial effects of CR may require only a short-term reduction in caloric intake.

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Correlation between increased atrial expression of genes related to fatty acid metabolism and autophagy in patients with chronic atrial fibrillation

PLoS ONE ◽

10.1371/journal.pone.0224713 ◽

2020 ◽

Vol 15 (4) ◽

pp. e0224713 ◽

Cited By ~ 2

Author(s):

Yasushige Shingu ◽

Shingo Takada ◽

Takashi Yokota ◽

Ryosuke Shirakawa ◽

Akira Yamada ◽

...

Keyword(s):

Atrial Fibrillation ◽

Fatty Acid ◽

Fatty Acid Metabolism ◽

Acid Metabolism ◽

Chronic Atrial Fibrillation ◽

Expression Of Genes

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Transfection of L6 myoblasts with adipocyte fatty acid-binding protein cDNA does not affect fatty acid uptake but disturbs lipid metabolism and fusion

Biochemical Journal ◽

10.1042/bj3290265 ◽

1998 ◽

Vol 329 (2) ◽

pp. 265-273 ◽

Cited By ~ 21

Author(s):

F. M. Clemens PRINSEN ◽

H. Jacques VEERKAMP

Keyword(s):

Fatty Acid ◽

Fatty Acid Metabolism ◽

Fatty Acid Binding Protein ◽

Acid Metabolism ◽

Binding Protein ◽

Fatty Acid Uptake ◽

Acid Uptake ◽

Fatty Acid Binding ◽

Transfected Cells ◽

Acid Binding Protein

We studied the involvement of fatty acid-binding protein (FABP) in growth, differentiation and fatty acid metabolism of muscle cells by lipofection of rat L6 myoblasts with rat heart (H) FABP cDNA or with rat adipocyte (A) FABP cDNA in a eukaryotic expression vector which contained a puromycin acetyltransferase cassette. Stable transfectants showed integration into the genome for all constructs and type-specific overexpression at the mRNA and protein level for the clones with H-FABP and A-FABP cDNA constructs. The rate of proliferation of myoblasts transfected with rat A-FABP cDNA was 2-fold higher compared with all other transfected cells. In addition, these myoblasts showed disturbed fusion and differentiation, as assessed by morphological examination and creatine kinase activity. Uptake rates of palmitate were equal for all clone types, in spite of different FABP content and composition. Palmitate oxidation over a 3 h period was similar in all clones from growth medium. After being cultured in differentiation medium, mock- and H-FABP-cDNA-transfected cells showed a lower fatty acid-oxidation rate, in contrast with A-FABP-cDNA-transfected clones. The ratio of [14C]palmitic acid incorporation into phosphatidylcholine and phosphatidylethanolamine of A-FABP-cDNA-transfected clones changed in the opposite direction in differentiation medium from that of mock- and H-FABP-cDNA-transfected clones. In conclusion, transfection of L6 myoblasts with A-FABP cDNA does not affect H-FABP content and fatty acid uptake, but changes fatty acid metabolism. The latter changes may be related to the observed fusion defect.

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Abstract 14844: Ampk is Required for Maintaining Atrial Metabolism and Oxidative Stress

Circulation ◽

10.1161/circ.142.suppl_3.14844 ◽

2020 ◽

Vol 142 (Suppl_3) ◽

Author(s):

Yina Ma ◽

Xiaohong Wu ◽

Xiaoyue Hu ◽

Gary Cline ◽

Fadi G Akar ◽

...

Keyword(s):

Oxidative Stress ◽

Atrial Fibrillation ◽

Fatty Acid ◽

Fatty Acid Metabolism ◽

Acid Metabolism ◽

Critical Role ◽

Acid Oxidation ◽

Fatty Acid Binding ◽

And Oxidative Stress ◽

Long Chain

Background: AMP-activated kinase (AMPK) has a critical role in cellular substrate and energy metabolism, regulating fatty acid oxidation, stimulating glucose transport and glycolysis. AMPK is crucial in the LV, preventing ischemic injury and heart failure. Atrial AMPK depletion induces atrial fibrillation in mice, but the role of AMPK in regulating atrial metabolism and oxidative stress is unknown. Methods: Atrial AMPK was selectively depleted in mice, utilizing sarcolipin-Cre mediated deletion of floxed α1 and α2 catalytic subunits (AMPKdKO). Floxed littermate mice were controls (CON). Microarray, immunoblotting, liquid chromatography-mass spectrometry (LC-MS), and electron microscope (EM) were used to access the gene, protein, metabolism, and mitochondria changes. Results: Pathway analysis of microarray data showed that fatty acid metabolism was downregulated in the AMPKdKO vs. CON atria (n=4 per group, p<0.0001). PGC1-α and downstream genes regulating fatty acid metabolism, including acyl-CoA thioesterase (ACOT), long-chain fatty acid-CoA ligase (ACSL), carnitine palmitoyltransferase 2 (CPT2), and fatty acid binding protein (FABP) were reduced in the AMPKdKO vs. CON atria (at 1 week of age). Atrial long-chain fatty acyl-CoA and acyl-carnitine levels were decreased (by LC-MS) in the AMPKdKO vs. CON atria (at 4 and 8 weeks of age) (n=3-4 per group, p<0.05). EM images showed evidence of swollen, broken and degraded mitochondrial in AMPKdKO atria (at 8 weeks age). Atrial expression of antioxidant enzymes, including SOD2 and PRDX3, was reduced (by immunoblotting) in AMPKdKO vs. CON atria (n=3-4, p<0.05). Conclusion: AMPK regulates critical mechanisms regulating atrial fatty acid metabolism and oxidative stress. Loss of atrial AMPK reduces the concentration of critical fatty acid intermediates for oxidative mitochondrial metabolism. These metabolic alterations may contribute to structural and electrical remodeling, and ensuing atrial fibrillation, that results from the loss of AMPK in the atria.

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Abstract 3: The Histone Methyltransferase Smyd1 is a Novel Transcriptional Regulator of Cardiac Fatty Acid Metabolism in Mice

Circulation Research ◽

10.1161/res.119.suppl_1.3 ◽

2016 ◽

Vol 119 (suppl_1) ◽

Author(s):

Junko S Warren ◽

Dane W Barton ◽

Mickey Miller ◽

Li Wang ◽

James Cox ◽

...

Keyword(s):

Gene Expression ◽

Fatty Acid ◽

Fatty Acid Metabolism ◽

Cardiac Dysfunction ◽

Acid Metabolism ◽

Transcriptional Start Site ◽

Cardiac Metabolism ◽

Histone Methyltransferase ◽

Tamoxifen Treatment ◽

Mrna Levels

Epigenetic control of metabolism in the healthy and diseased heart remains poorly understood. We recently demonstrated that chromatin-bound Smyd1, a muscle-specific histone methyltransferase, is significantly upregulated in a mouse model of pressure overload-induced heart failure (HF) and that inducible, cardiac-specific Smyd1 knock-out (Smyd1-KO) mice develop cellular hypertrophy and fulminate HF. Bioinformatic analysis of transcripts differentially regulated in these mice revealed that cardiac metabolism was the most perturbed biological function in the heart. However, it was not clear whether alterations in cardiac metabolism were a direct consequence of Smyd1 deletion or were secondary to developed HF. Here we hypothesized that Smyd1 directly regulates cardiac metabolism; the effects of which should be detectable in Smyd1-KO mice before overt cardiac dysfunction. To test this hypothesis we performed unbiased metabolomic analysis of Smyd1-KO mice using GC/MS and MS/MS (n=9 control, n=10 KO) combined with targeted gene expression analysis. Our results showed significant changes in the metabolic profile of Smyd1-KO mice at the earliest time point (3 weeks after tamoxifen treatment) in which Smyd1 protein expression was significantly reduced while cardiac function remained normal. The most profound difference, in energetics-associated pathways in these mice, was found in fatty acid β-oxidation, manifested by the decreased myocardial content of carnitine and free fatty acids and downregulation of their transporters, OCTN2 and CD36. In addition, mRNA levels of the PPAR-α complex (PPAR-α;RXR-α;PGC-1α), an established regulator of fatty acid β-oxidation, and its target genes (CPT1b;CD36;Acox1;MCAD) were significantly reduced in Smyd1-KO mice prior to the onset of cardiac dysfunction (all p<0.05). To identify whether Smyd1 directly controls gene expression of PPAR-α, we examined the PPAR-α loci using chromatin-immunoprecipitation followed by qPCR and observed significant binding of Smyd1 upstream of the PPAR-α transcriptional start site. Overall, this study identifies Smyd1 as a novel regulator of fatty acid metabolism and suggests that Smyd1 controls cardiac energetics directly by regulating gene expression of PPAR-α.

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Abstract O-1: Klf5 Regulates Cardiac Pparα and Med13 and affects Cardiac Fatty Acid Metabolism And Obesity

Circulation Research ◽

10.1161/res.115.suppl_1.o-1 ◽

2014 ◽

Vol 115 (suppl_1) ◽

Author(s):

Konstantinos Drosatos ◽

Nina Pollak ◽

Panagiotis Ntziachristos ◽

Chad M Trent ◽

Yunying Hu ◽

...

Keyword(s):

Gene Expression ◽

Fatty Acid ◽

Fatty Acid Metabolism ◽

Binding Sites ◽

Transcription Initiation ◽

Acid Metabolism ◽

Gene Promoter ◽

Initiation Site ◽

White Adipocytes ◽

Metabolic Role

Krüppel-like factors (KLF) have been associated with metabolic phenotypes. Our study focused on the metabolic role of cardiac KLF5, as it showed the highest increase among all KLFs that were detected by whole genome microarrays of energy-starved hearts obtained from lipopolysaccharide (LPS)-treated mice. Analysis of ppara promoter indicated two potential binding sites for c-Jun (AP-1 sites), the transcriptional factor that is activated by LPS and reduces cardiac PPARα expression: −792/-772 bp and −719/-698 bp prior to the transcription initiation site. This analysis showed that both AP-1 sites overlap with potential KLF-binding sites. Adenovirus-mediated expression of constitutively active c-Jun in a mouse cardiomyocyte cell line (HL-1) reduced PPARα gene expression, while treatment with Ad-KLF5 had the opposite effect. Chromatin immunoprecipitation analysis (ChIP) showed that c-Jun binds both −792/-772 bp and −719/-698 sites of ppara promoter while KLF5 binds on −792/-772 bp. ChIP analysis also showed that LPS promotes c-Jun binding on −792/-772 bp, which prohibits occupation of this region by KLF5. A cardiomyocyte-specific KLF5 knockout mouse (αMHC-KLF5-/-) had normal cardiac function but reduced cardiac expression of PPARα (50%) and other fatty acid metabolism-associated genes such as CD36 (40%), LpL (20%), PGC1α (45%), AOX (28%) and Cpt1 (45%). High fat diet (HFD)-fed αMHC-KLF5-/- mice had a more profound body weight increase (35%) compared to HFD-fed WT mice (15%), as well as larger white adipocytes and brown adipocytes (H&E) and increased hepatic neutral lipid accumulation (Oil-Red-O). The obesogenic effect of cardiomyocyte-specific deletion of KLF5 resembles the phenotype of the αMHC-MED13-/- mice. We showed that KLF5 ablation reduced cardiac MED13 levels despite lack of changes in the expression levels of miR-208, a known regulator of MED13. Infection of HL-1 cells with Ad-KLF5 increased MED13 gene expression. ChIP identified a KLF5 binding site on med13 gene promoter region (-730/-714 bp). Thus, KLF5 regulates cardiac PPARα and MED13 and affects cardiac and systemic fatty acid metabolism and obesity, thus indicating KLF5 as a potential target for cardiac dysfunction associated with energetic complications, as well as for obesity

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