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

Circulation ◽  
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.

A null mutation in skeletal muscle FAT/CD36 reveals its essential role in insulin- and AICAR-stimulated fatty acid metabolism

2007 ◽  
Vol 292 (6) ◽  
pp. E1740-E1749 ◽  
Author(s):  
Arend Bonen ◽  
Xiao-Xia Han ◽  
Daphna D. J. Habets ◽  
Maria Febbraio ◽  
Jan F. C. Glatz ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Fatty Acid Metabolism ◽  
Acid Metabolism ◽  
Critical Role ◽  
Acid Oxidation ◽  
Fatty Acid Binding ◽  
Acid Esterification ◽  
White Gastrocnemius ◽  
Fatty Acid Esterification

Fatty acid translocase (FAT)/CD36 is involved in regulating the uptake of long-chain fatty acids into muscle cells. However, the contribution of FAT/CD36 to fatty acid metabolism remains unknown. We examined the role of FAT/CD36 on fatty acid metabolism in perfused muscles (soleus and red and white gastrocnemius) of wild-type (WT) and FAT/CD36 null (KO) mice. In general, in muscles of KO mice, 1) insulin sensitivity and 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside (AICAR) sensitivity were normal, 2) key enzymes involved in fatty acid oxidation were altered minimally or not at all, and 3) except for an increase in soleus muscle FATP1 and FATP4, these fatty acid transporters were not altered in red and white gastrocnemius muscles, whereas plasma membrane-bound fatty acid binding protein was not altered in any muscle. In KO muscles perfused under basal conditions (i.e., no insulin, no AICAR), rates of hindquarter fatty acid oxidation were reduced by 26%. Similarly, in oxidative but not glycolytic muscles, the basal rates of triacylglycerol esterification were reduced by 40%. When muscles were perfused with insulin, the net increase in fatty acid esterification was threefold greater in the oxidative muscles of WT mice compared with the oxidative muscles in KO mice. With AICAR-stimulation, the net increase in fatty acid oxidation by hindquarter muscles was 3.7-fold greater in WT compared with KO mice. In conclusion, the present studies demonstrate that FAT/CD36 has a critical role in regulating fatty acid esterification and oxidation, particularly during stimulation with insulin or AICAR.

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

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.

scholarly journals RiboTag translatomic profiling of Drosophila oenocytes under aging and oxidative stress

2018 ◽  
Author(s):  
Kerui Huang ◽  
Wenhao Chen ◽  
Fang Zhu ◽  
Hua Bai
Keyword(s):  
Oxidative Stress ◽  
Fatty Acid ◽  
Lipid Metabolism ◽  
Stress Response ◽  
Fatty Acid Metabolism ◽  
Acid Metabolism ◽  
Fat Body ◽  
Mapk Signaling ◽  
Age Related ◽  
And Oxidative Stress

AbstractBackgroundAging is accompanied with loss of tissue homeostasis and accumulation of cellular damages. As one of the important metabolic centers, aged liver shows altered lipid metabolism, impaired detoxification pathway, increased inflammation and oxidative stress response. However, the mechanisms for these age-related changes still remain unclear. In fruit flies, Drosophila melanogaster, liver-like functions are controlled by two distinct tissues, fat body and oenocytes. Although the role of fat body in aging regulation has been well studied, little is known about how oenocytes age and what are their roles in aging regulation. To address these questions, we used cell-type-specific ribosome profiling (RiboTag) to study the impacts of aging and oxidative stress on oenocyte translatome in Drosophila.ResultsWe show that aging and oxidant paraquat significantly increased the levels of reactive oxygen species (ROS) in adult oenocytes of Drosophila, and aged oenocytes exhibited reduced sensitivity to paraquat treatment. Through RiboTag sequencing, we identified 3324 and 949 differentially expressed genes in oenocytes under aging and paraquat treatment, respectively. Aging and paraquat exhibit both shared and distinct regulations on oenocyte translatome. Among all age-regulated genes, mitochondrial, proteasome, peroxisome, fatty acid metabolism, and cytochrome P450 pathways were down-regulated, whereas DNA replication and glutathione metabolic pathways were up-regulated. Interestingly, most of the peroxisomal genes were down-regulated in aged oenocytes, including peroxisomal biogenesis factors and beta-oxidation genes. Further analysis of the oenocyte translatome showed that oenocytes highly expressed genes involving in liver-like processes (e.g., ketogenesis). Many age-related transcriptional changes in oenocytes are similar to aging liver, including up-regulation of Ras/MAPK signaling pathway and down-regulation of peroxisome and fatty acid metabolism.ConclusionsOur oenocyte-specific translatome analysis identified many genes and pathways that are shared between Drosophila oenocytes and mammalian liver, highlighting the molecular and functional similarities between the two tissues. Many of these genes are altered in both aged oenocytes and aged liver, suggesting a conserved molecular mechanism underlying oenocyte and liver aging. Thus, our translatome analysis will contribute significantly to the understanding of oenocyte biology, and its role in lipid metabolism, stress response and aging regulation.

Abstract 271: Reduced Expression of the Cardiac Sodium Channel Nav1.5 Triggers Enhanced Fatty Acid Metabolism and Oxidative Stress

2019 ◽  
Vol 125 (Suppl_1) ◽  
Author(s):  
Ryan L Boudreau ◽  
Xiaoming Zhang ◽  
Jared M McLendon ◽  
William Kutschke ◽  
Ethan J Anderson ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Fatty Acid ◽  
Sodium Channel ◽  
Fatty Acid Metabolism ◽  
Acid Metabolism ◽  
Cardiac Sodium Channel ◽  
And Oxidative Stress

II. Cytochrome P-450 enzymes and oxidative stress

2001 ◽  
Vol 281 (5) ◽  
pp. G1135-G1139 ◽  
Author(s):  
Graham Robertson ◽  
Isabelle Leclercq ◽  
Geoffrey C. Farrell
Keyword(s):  
Oxidative Stress ◽  
Fatty Acid ◽  
Molecular Oxygen ◽  
Hepatic Steatosis ◽  
Nonalcoholic Steatohepatitis ◽  
Acid Oxidation ◽  
Cellular Injury ◽  
Second Hit ◽  
Cytochrome P 450 ◽  
And Oxidative Stress

Oxidative stress is present in the liver of humans with steatosis and nonalcoholic steatohepatitis (NASH) and is a plausible mediator of cellular injury, inflammatory recruitment, and fibrogenesis. CYPs 2E1 and 4A are the microsomal oxidases involved with fatty acid oxidation. Both enzymes can reduce molecular oxygen to produce prooxidant species, which, if not countered efficiently by antioxidants, create oxidative stress. In this theme article, we present the evidence that, in the context of hepatic steatosis, CYPs 2E1 and 4A could generate the “second hit” of cellular injury, particularly when antioxidant reserves are depleted, and propose ways in which this could contribute to the pathogenesis of NASH.

scholarly journals Phenolic Compounds Reduce the Fat Content in Caenorhabditis elegans by Affecting Lipogenesis, Lipolysis, and Different Stress Responses

2020 ◽  
Vol 13 (11) ◽  
pp. 355
Author(s):  
Paula Aranaz ◽  
David Navarro-Herrera ◽  
María Zabala ◽  
Ana Romo-Hualde ◽  
Miguel López-Yoldi ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Fatty Acid ◽  
Phenolic Compounds ◽  
Fatty Acid Metabolism ◽  
Acid Metabolism ◽  
Lipid Mobilization ◽  
C Elegans ◽  
Unfolded Protein ◽  
Reducing Activity ◽  
Protein Response

Supplementation with bioactive compounds capable of regulating energy homeostasis is a promising strategy to manage obesity. Here, we have screened the ability of different phenolic compounds (myricetin, kaempferol, naringin, hesperidin, apigenin, luteolin, resveratrol, curcumin, and epicatechin) and phenolic acids (p-coumaric, ellagic, ferulic, gallic, and vanillic acids) regulating C. elegans fat accumulation. Resveratrol exhibited the strongest lipid-reducing activity, which was accompanied by the improvement of lifespan, oxidative stress, and aging, without affecting worm development. Whole-genome expression microarrays demonstrated that resveratrol affected fat mobilization, fatty acid metabolism, and unfolded protein response of the endoplasmic reticulum (UPRER), mimicking the response to calorie restriction. Apigenin induced the oxidative stress response and lipid mobilization, while vanillic acid affected the unfolded-protein response in ER. In summary, our data demonstrates that phenolic compounds exert a lipid-reducing activity in C. elegans through different biological processes and signaling pathways, including those related with lipid mobilization and fatty acid metabolism, oxidative stress, aging, and UPR-ER response. These findings open the door to the possibility of combining them in order to achieve complementary activity against obesity-related disorders.

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