Intramyocellular Fatty-Acid Metabolism Plays a Critical Role in Mediating Responses to Dietary Restriction in Drosophila melanogaster

Abstract Fatty acid metabolism governs multiple intracellular signaling pathways in many cell types, but its role in hematopoietic stem cells (HSCs) is largely unknown. Herein, we establish a critical role for 12/15-lipoxygenase (12/15-LOX)–mediated unsaturated fatty acid metabolism in HSC function. HSCs from 12/15-LOX–deficient mice are severely compromised in their capacity to reconstitute the hematopoietic compartment in competitive and serial reconstitution assays. Furthermore, we demonstrate that 12/15-LOX is required for the maintenance of long-term HSC quiescence and number. The defect in HSCs is cell-autonomous and associated with a selective reduction in 12/15-LOX–mediated generation of bioactive lipid mediators and reactive oxygen species and with a decrease in canonical Wnt signaling as measured by nuclear β-catenin staining. These results have implications for development, aging, and transformation of the hematopoietic compartment.

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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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Fatty acid metabolism in Drosophila melanogaster: Interaction between dietary fatty acids and De novo synthesis

Comparative Biochemistry and Physiology ◽

10.1016/0010-406x(67)90455-0 ◽

1967 ◽

Vol 21 (3) ◽

pp. 587-600 ◽

Cited By ~ 56

Author(s):

Alec D. Keith

Keyword(s):

Fatty Acids ◽

Drosophila Melanogaster ◽

Fatty Acid ◽

Fatty Acid Metabolism ◽

Acid Metabolism ◽

De Novo ◽

Dietary Fatty Acids ◽

De Novo Synthesis

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

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00579.2006 ◽

2007 ◽

Vol 292 (6) ◽

pp. E1740-E1749 ◽

Cited By ~ 91

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.

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The Influence of Lactate and Dipyridamole on Myocardial Fatty Acid Metabolism in Man, Traced with 123l-17-lodo-heptadecanoic Acid

Nuklearmedizin ◽

10.1055/s-0038-1629509 ◽

1990 ◽

Vol 29 (01) ◽

pp. 28-34 ◽

Cited By ~ 1

Author(s):

F. C. Visser ◽

M. J. van Eenige ◽

G. Westera ◽

J. P. Roos ◽

C. M. B. Duwel

Keyword(s):

Fatty Acid ◽

Fatty Acid Metabolism ◽

Acid Metabolism ◽

Time Activity ◽

Time Value ◽

Myocardial Fatty Acid Metabolism ◽

Coronary Vasodilatation ◽

Activity Curve ◽

Normal Human ◽

Plasma Lactate Level

Changes in myocardial metabolism can be detected externally by registration of time-activity curves after administration of radioiodinated fatty acids. In this scintigraphic study the influence of lactate on fatty acid metabolism was investigated in the normal human myocardium, traced with 123l-17-iodoheptadecanoic acid (123l-17-HDA). In patients (paired, n = 7) lactate loading decreased the uptake of 123l-17-HDA significantly from 27 (control: 22-36) to 20 counts/min/pixel (16-31; p <0.05 Wilcoxon). The half-time value increased to more than 60 rriin (n = 5), oxidation decreased from 61 to 42%. Coronary vasodilatation, a well-known side effect of lactate loading, was studied separately in a dipyridamole study (paired, n = 6). Coronary vasodilatation did not influence the parameters of the time-activity curve. These results suggest that changes in plasma lactate level as occurring, among other effects, during exercise will influence the parameters of dynamic 123l-17-HDA scintigraphy of the heart.

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