Targeting The Interactions Of Fatty Acid Metabolism With PI3K/mTOR and MAPK As a Novel Therapeutic Strategy In Diffuse Large B-Cell Lymphoma (DLBCL)

Abstract Background Fatty acid metabolism is altered in several cancers, which includes de novo synthesis by fatty acid synthase (FASN) and increased utilization of fatty acids via β-oxidation to meet cellular energy requirements. PI3K and MEK/ERK signal transduction are primary biological pathways that activate tumor-related fatty acid metabolism. Notably, these concepts have emerged primarily from solid tumor studies; there is a comparative paucity of data in lymphoma. We examined the functional roles of fatty acid metabolism in DLBCL cells and their interaction with oncogenic signal transduction pathways including PI3K, MEK/ERK and hypoxia inducible factor-1 alpha (HIF-1a). We also investigated potential therapeutic implications of targeting fatty acid metabolism for the treatment of DLBCL. Methods DLBCL cell lines OCI-LY3, OCI-LY19, SUDHL4, and SUDHL10 were examined in this study. Cerulenin (FASN inhibitor), Orlistat (FASN and LPL inhibitor), BEZ-235 (Dual PI3K/mTOR inhibitor), AZD6244 (MEK inhibitor) were used to study the effects of enzyme inhibition on lipid metabolism, cell signaling and cell death. We assessed cell viability with the MTT assay and apoptosis by flow cytometric analysis of Annexin-V/propidium iodide (PI). FASN or LPL mRNAs were quantified in DLBCL cell lines by quantitative RT-PCR as well as through gene expression profiling (GEP) analysis (by cell of origin) using the CaBIG dataset. Further, FASN and associated signaling pathways (MEK, ERK, and HIF-1a) were analyzed by Western blot. Finally, for investigation of potential interactions between FASN and HIF-1a or MAPK signaling, we utilized short hairpin RNA interference (shRNA) to knock out (KO) desired pathways. Results GEP analysis showed that genes related to fatty acid synthesis and mTOR were more prominently expressed in germinal center (GC) DLBCL (p=0.0006 vs GC control and p=0.0001 vs non-GC DLBCL), whereas genes involved in utilization of fatty acid for energy, PI3K and MAPK were preferentially expressed in non-GC DLBCL (p<0.0001 vs non-GC control and GC DLBCL). Protein level expression of FASN and CPT1 (relevant to β-oxidation) was readily detectable in all DLBCL cell lines, while the expression of LPL was low, except in SUDHL10 cells. We next examined FASN expression following KO of MEK, ERK, and/or HIF-1a using shRNA in OCI-LY3 and SUDHL10 cells. HIF-1a KO in OCI-LY3 cells and MEK, ERK KO in SUDHL10 significantly decreased FASN expression. Similarly, pharmacological inhibition of PI3K/mTOR or MEK using novel small molecule agents BEZ-235 or AZD6244 (selumetinib), we observed down-regulation of both HIF-1a and FASN expression. Treatment with BEZ-235 under fatty acid deprived conditions resulted in synergistic cell death 60% in OCI-LY3, compared to 25% with BEZ-235 alone. Additionally inhibition of MEK/ERK using AZD6244 or U0126 also resulted in down-regulation of CPT1 relevant to β-oxidation. Pharmacologic treatment with cerulenin, however, resulted in inhibition of MEK and ERK phosphorylation and apoptosis in SUDHL4 and OCI-LY3 cells. Furthermore, treatment with AZD6244 or cerulenin both resulted in time- and dose-dependent cell death (Annexin-V/PI) and decreased proliferation (by MTT) in GC and non-GC DLBCL cell lines (P<0.001). Conclusions Altogether, we demonstrated that fatty acid metabolism is highly upregulated in DLBCL and that there was preferential gene expression in DLBCL cells in part according to cell of origin. Further, PI3K/mTOR, MAPK and HIF-1a constitutively activated oncogenic pathways in DLBCL appeared here to directly regulate fatty acid metabolism. In addition, we showed that targeting fatty acid metabolism may be harnessed as a potential therapeutic strategy. Continued investigation is warranted to delineate the mechanisms through which MAPK and HIF-1a regulate FASN expression and to determine the in vivo implications of FASN inhibition on DLBCL tumor growth. Disclosures: No relevant conflicts of interest to declare.

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Fatty Acid Metabolism in Diffuse Large B-Cell Lymphoma (DLBCL): Interaction with Oncogenic Cell Signaling Pathways and the Identification of a Novel Treatment Paradigm.

Blood ◽

10.1182/blood.v120.21.2711.2711 ◽

2012 ◽

Vol 120 (21) ◽

pp. 2711-2711

Author(s):

Ravi Dashnamoorthy ◽

Frederick Lansigan ◽

Wilson L Davis ◽

Nancy Kuemmerle ◽

William B Kinlaw ◽

...

Keyword(s):

Signal Transduction ◽

Cell Death ◽

Fatty Acid ◽

Cell Signaling ◽

Signaling Pathways ◽

Cell Lines ◽

Fatty Acid Metabolism ◽

Acid Metabolism ◽

Cell Of Origin ◽

Rt Pcr

Abstract Abstract 2711 Background: Fatty acid synthase (FASN) is a key enzyme of fatty acid synthesis and is upregulated in many cancers. Increased FASN in cancer is associated with poor prognosis, while inhibition of FASN results in cancer cell death. The MEK/ERK signal transduction is one of the primary pathways that activate tumor-related FASN. Lipoprotein lipase (LPL) is also involved in fatty acid metablishm as it releases free fatty acid (FFA) from circulating lipoproteins, making them available for cellular uptake. Notably, these concepts have emerged primarily from solid tumor studies; there is a comparative paucity of data in lymphoma. We examined the functional roles of FASN and LPL in DLBCL cells and their interaction with oncogenic signal transduction pathways including MEK/ERK and an upstream target, hypoxia inducible factor-1 alpha (HIF-1a). We also investigated potential therapeutic implications of targeting fatty acid metabolism for the treatment of DLBCL. Methods: We used the DLBCL cell lines OCI-LY3, OCI-LY19, SUDHL4, and SUDHL10 in normoxic or hypoxic (0.2% O2) conditions. Cerulenin (FASN inhibitor) and Orlistat (FASN and LPL inhibitor) were utilized to examine the effect of fatty acid enzyme inhibition on cell signaling and cell death. We assessed cell viability with the MTT assay and apoptosis by flow cytometric analysis of Annexin-V/propidium iodide (PI). FASN and LPL mRNAs were quantified in DLBCL cell lines by RT-PCR as well as through gene expression profiling (GEP) analysis (by cell of origin) using the CaBIG dataset. Further, FASN and associated signaling pathways (MEK, ERK, and HIF-1a) were analyzed by Western blot. Finally, for investigation of potential interactions between FASN and HIF-1a, or MAPK signaling, we utilized short hairpin RNA interference (shRNA) to knock down (KD) pathways of interest. Results: FASN protein expression was readily detectable in all DLBCL cell lines in normoxia, while the expression of LPL was barely detectable in most cells, except in SUDHL10 and only in hypoxic conditions. RT-PCR showed that all DLBCL cell lines tested expressed high levels of FASN mRNA, while minimal levels of LPL could be detected; GEP showed that FASN was expressed more prominently in germinal center (GC) DLBCL (p=0.0006 vs GC control and p=0.0001 vs non-GC DLBCL), whereas LPL was preferentially expressed in non-GC DLBCL (p<0.0001 vs non-GC control and GC DLBCL). We next examined FASN expression following KD of MEK, ERK, or HIF-1a using shRNA in OCI-LY3 and SUDHL10 cells. HIF-1a KD significantly decreased FASN expression; this result was most prominent in OCI-LY3 cells, although it was also evident in SUDHL10. Interestingly, MEK and ERK KDs had minimal effect on FASN or LPL. Pharmacologic treatment with cerulenin, however, resulted in inhibition of MEK and ERK phosphorylation in OCI-LY3 cells. Additionally, treatment with Cerulenin or Orlistat (0.25–4 μg/mL for 48 hours) resulted in dose-dependent cytotoxicity across several DLBCL cell lines (OCI-LY3, SUDHL4, and SUDHL10) with an approximate IC50 of 1μg/mL in all lines. Furthermore, treatment with Cerulenin resulted in induction of apoptosis, which was mediated by caspase cleavage (caspases 3, 8 and 9) in SUDHL4 and OCI-LY3 cells. Conclusions: We demonstrated that FASN is constitutively activated in DLBCL with expression in part dependent on cell of origin, while LPL protein or message were mostly down-regulated. HIF-1a is a constitutively activated oncogenic pathway in DLBCL (Evens AM, et al. Br J Haematol 2008) and it appeared here to directly regulate FASN expression. In addition, we showed that targeting fatty acid metabolism may be harnessed as a potential therapeutic strategy. Further investigations are required to delineate the mechanisms through which MAPK and HIF-1a regulate FASN expression and to determine the in vivo implications of FASN inhibition on DLBCL tumor growth. Disclosures: No relevant conflicts of interest to declare.

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Lipid and glucose metabolism in hepatocyte cell lines and primary mouse hepatocytes: a comprehensive resource for in vitro studies of hepatic metabolism

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00365.2018 ◽

2019 ◽

Vol 316 (4) ◽

pp. E578-E589 ◽

Cited By ~ 15

Author(s):

Shilpa R. Nagarajan ◽

Moumita Paul-Heng ◽

James R. Krycer ◽

Daniel J. Fazakerley ◽

Alexandra F. Sharland ◽

...

Keyword(s):

Fatty Acid ◽

Glucose Metabolism ◽

Cell Lines ◽

Fatty Acid Metabolism ◽

Acid Metabolism ◽

Primary Hepatocytes ◽

Primary Mouse Hepatocytes ◽

Primary Mouse ◽

Mouse Hepatocytes

The liver is a critical tissue for maintaining glucose, fatty acid, and cholesterol homeostasis. Primary hepatocytes represent the gold standard for studying the mechanisms controlling hepatic glucose, lipid, and cholesterol metabolism in vitro. However, access to primary hepatocytes can be limiting, and therefore, other immortalized hepatocyte models are commonly used. Here, we describe substrate metabolism of cultured AML12, IHH, and PH5CH8 cells, hepatocellular carcinoma-derived HepG2s, and primary mouse hepatocytes (PMH) to identify which of these cell lines most accurately phenocopy PMH basal and insulin-stimulated metabolism. Insulin-stimulated glucose metabolism in PH5CH8 cells, and to a lesser extent AML12 cells, responded most similarly to PMH. Notably, glucose incorporation in HepG2 cells were 14-fold greater than PMH. The differences in glucose metabolic activity were not explained by differential protein expression of key regulators of these pathways, for example glycogen synthase and glycogen content. In contrast, fatty acid metabolism in IHH cells was the closest to PMHs, yet insulin-responsive fatty acid metabolism in AML12 and HepG2 cells was most similar to PMH. Finally, incorporation of acetate into intracellular-free cholesterol was comparable for all cells to PMH; however, insulin-stimulated glucose conversion into lipids and the incorporation of acetate into intracellular cholesterol esters were strikingly different between PMHs and all tested cell lines. In general, AML12 cells most closely phenocopied PMH in vitro energy metabolism. However, the cell line most representative of PMHs differed depending on the mode of metabolism being investigated, and so careful consideration is needed in model selection.

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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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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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Interception of host fatty acid metabolism by mycobacteria under hypoxia to suppress anti-TB immunity

Cell Discovery ◽

10.1038/s41421-021-00301-1 ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Hua Yang ◽

Fei Wang ◽

Xinya Guo ◽

Feng Liu ◽

Zhonghua Liu ◽

...

Keyword(s):

Fatty Acid ◽

Fatty Acid Metabolism ◽

Therapeutic Strategy ◽

Acid Metabolism ◽

Latent Tuberculosis ◽

Host Immunity ◽

Acetyl Coa ◽

Nutrient Sources ◽

Mycobacterial Genome ◽

Mycobacterial Protein

AbstractPathogenic mycobacteria induce the formation of hypoxic granulomas during latent tuberculosis (TB) infection, in which the immune system contains, but fails to eliminate the mycobacteria. Fatty acid metabolism-related genes are relatively overrepresented in the mycobacterial genome and mycobacteria favor host-derived fatty acids as nutrient sources. However, whether and how mycobacteria modulate host fatty acid metabolism to drive granuloma progression remains unknown. Here, we report that mycobacteria under hypoxia markedly secrete the protein Rv0859/MMAR_4677 (Fatty-acid degradation A, FadA), which is also enriched in tuberculous granulomas. FadA acts as an acetyltransferase that converts host acetyl-CoA to acetoacetyl-CoA. The reduced acetyl-CoA level suppresses H3K9Ac-mediated expression of the host proinflammatory cytokine Il6, thus promoting granuloma progression. Moreover, supplementation of acetate increases the level of acetyl-CoA and inhibits the formation of granulomas. Our findings suggest an unexpected mechanism of a hypoxia-induced mycobacterial protein suppressing host immunity via modulation of host fatty acid metabolism and raise the possibility of a novel therapeutic strategy for TB infection.

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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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MALDI Mass Spectrometry Imaging of Lipids and Gene Expression Reveals Differences in Fatty Acid Metabolism between Follicular Compartments in Porcine Ovaries

Biology ◽

10.3390/biology4010216 ◽

2015 ◽

Vol 4 (1) ◽

pp. 216-236 ◽

Cited By ~ 14

Author(s):

Svetlana Uzbekova ◽

Sebastien Elis ◽

Ana-Paula Teixeira-Gomes ◽

Alice Desmarchais ◽

Virginie Maillard ◽

...

Keyword(s):

Gene Expression ◽

Mass Spectrometry ◽

Fatty Acid ◽

Fatty Acid Metabolism ◽

Mass Spectrometry Imaging ◽

Acid Metabolism ◽

Maldi Mass Spectrometry ◽

Maldi Mass Spectrometry Imaging

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Global Gene Expression Profiling in PPAR-γAgonist-Treated Kidneys in an Orthologous Rat Model of Human Autosomal Recessive Polycystic Kidney Disease

PPAR Research ◽

10.1155/2012/695898 ◽

2012 ◽

Vol 2012 ◽

pp. 1-10 ◽

Cited By ~ 5

Author(s):

Daisuke Yoshihara ◽

Masanori Kugita ◽

Tamio Yamaguchi ◽

Harold M. Aukema ◽

Hiroki Kurahashi ◽

...

Keyword(s):

Gene Expression ◽

Cell Cycle ◽

Cell Proliferation ◽

Fatty Acid ◽

Kidney Disease ◽

Fatty Acid Metabolism ◽

Acid Metabolism ◽

Interstitial Fibrosis ◽

Global Gene Expression ◽

Polycystic Kidney

Kidneys are enlarged by aberrant proliferation of tubule epithelial cells leading to the formation of numerous cysts, nephron loss, and interstitial fibrosis in polycystic kidney disease (PKD). Pioglitazone (PIO), a PPAR-γagonist, decreased cell proliferation, interstitial fibrosis, and inflammation, and ameliorated PKD progression in PCK rats (Am. J. Physiol.-Renal, 2011). To explore genetic mechanisms involved, changes in global gene expression were analyzed. By Gene Set Enrichment Analysis of 30655 genes, 13 of the top 20 downregulated gene ontology biological process gene sets and six of the top 20 curated gene set canonical pathways identified to be downregulated by PIOtreatment were related to cell cycle and proliferation, including EGF, PDGF and JNK pathways. Their relevant pathways were identified using the Kyoto Encyclopedia of Gene and Genomes database. Stearoyl-coenzyme A desaturase 1 is a key enzyme in fatty acid metabolism found in the top 5 genes downregulated by PIO treatment. Immunohistochemical analysis revealed that the gene product of this enzyme was highly expressed in PCK kidneys and decreased by PIO. These data show that PIO alters the expression of genes involved in cell cycle progression, cell proliferation, and fatty acid metabolism.

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

10.1101/815126 ◽

2019 ◽

Author(s):

Yasushige Shingu ◽

Shingo Takada ◽

Takashi Yokota ◽

Ryosuke Shirakawa ◽

Akira Yamada ◽

...

Keyword(s):

Gene Expression ◽

Atrial Fibrillation ◽

Fatty Acid ◽

Fatty Acid Metabolism ◽

Acid Metabolism ◽

Right Atrial ◽

Fatty Acid Transport ◽

Acid Uptake ◽

Fatty Acid Binding ◽

Expression Of Genes

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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