Abstract 233: Metabolic Trapping Effects of ACS1 for Fatty Acid Uptake and Intracellular Trafficking are Different in Hearts of Males and Females

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Joseph R Goldenberg ◽  
Xuerong Wang ◽  
Andrew N Carley ◽  
E. Douglas Lewandowski
Keyword(s):  
Fatty Acid ◽  
Acyl Chain ◽  
Female Gender ◽  
Fatty Acid Uptake ◽  
Acid Uptake ◽  
Membrane Transport Proteins ◽  
Fatty Acid Transporter ◽  
Males And Females ◽  
Two Phases ◽  
Lcfa Uptake

Disruption of cardiomyocyte lipid metabolism has been observed in the responses to both pathogenic and nutrient stresses in human patients and animal models, with distinct sex differences. This investigation examined cardiac acyl CoA synthetase-1 (ACS)-mediated, LCFA uptake and trafficking with hearts of male and female mice. Isolated mouse hearts with cardiac specific overexpression of ACS1 (MHC-ACS) and non-transgenic littermates (NTG) were perfused with buffer containing 13C palmitate, 10 mM glucose, and 1 mM lactate. Dynamic 13C NMR elucidated the two phases of LCFA incorporation into triacylglycerol (TAG). The time constant (τ) of the initial exponential phase, corresponding to LCFA trans-sarcolemmal uptake, was lower, indicating faster LCFA uptake and esterification in male ACS hearts compared to NTG males (ACS male τ = 1.59±0.67 min vs NTG male τ = 2.85±0.90 min, P<0.05). Consistent with greater metabolic trapping, acyl CoA content was 470% higher in male ACS hearts (NTG male 57.5±9.4 vs ACS male 327.4±42 pmol/mg protein. P<0.001). Despite no differences in ACS content, NTG females displayed faster uptake than NTG males at a rate similar to ACS males, which was reversed by ovariectomy (OVX) indicating an estrogen dependent response (NTG female τ = 1.56±0.46 min, P<0.05 vs NTG OVX female τ = 3.02±0.77 min, P<0.05). Despite prior reports of ACS localization distal from the sarcolemma, ACS level and female gender both independently accelerated LCFA uptake without affecting TAG content or turnover. The data are consistent with metabolic trapping to facilitate LCFA uptake due to ACS activity. ACS also leads to higher total ceramide in hearts, with specific elevation of C18 and C22 in both genders, C24 in males, and C20 in females (male P<0.05; female P<0.01). ACS overexpression induced lower content of the cardiac fatty acid transporter (FATP) isoform, FATP6, indicating cooperative regulation of LCFA uptake between membrane transport proteins and intracellular acyl chain activation (P<0.05 male; P<0.001 female and female OVX). These results demonstrate that perturbation of LCFA metabolism though facilitated metabolic trapping by ACS1 affects sarcolemma transporter expression and induces the conversion of the CoA activated LCFA to ceramide.

Insulin induces the translocation of the fatty acid transporter FAT/CD36 to the plasma membrane

2002 ◽  
Vol 282 (2) ◽  
pp. E491-E495 ◽  
Author(s):  
Joost J. F. P. Luiken ◽  
David J. Dyck ◽  
Xiao-Xia Han ◽  
Narendra N. Tandon ◽  
Yoga Arumugam ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Fatty Acid ◽  
Muscle Contraction ◽  
Kinase Inhibitor ◽  
Fatty Acid Uptake ◽  
Fatty Acid Transport ◽  
Acid Uptake ◽  
Hindlimb Muscles ◽  
Fatty Acid Transporter ◽  
Acid Transporter

It is well known that muscle contraction and insulin can independently translocate GLUT-4 from an intracellular depot to the plasma membrane. Recently, we have shown that the fatty acid transporter FAT/CD36 is translocated from an intracellular depot to the plasma membrane by muscle contraction (<30 min) (Bonen et al. J Biol Chem 275: 14501–14508, 2000). In the present study, we examined whether insulin also induced the translocation of FAT/CD36 in rat skeletal muscle. In studies in perfused rat hindlimb muscles, we observed that insulin increased fatty acid uptake by +51%. Insulin increased the rate of palmitate incorporation into triacylglycerols, diacylglycerols, and phospholipids ( P < 0.05) while reducing muscle palmitate oxidation ( P < 0.05). Perfusing rat hindlimb muscles with insulin increased plasma membrane FAT/CD36 by +48% ( P < 0.05), whereas concomitantly the intracellular FAT/CD36 depot was reduced by 68% ( P < 0.05). These insulin-induced effects on FAT/CD36 translocation were inhibited by the phosphatidylinositol 3-kinase inhibitor LY-294002. Thus these studies have shown for the first time that insulin can induce the translocation of FAT/CD36 from an intracellular depot to the plasma membrane.This reveals a previously unknown level of regulation of fatty acid transport by insulin and may well have important consequences in furthering our understanding of the relation between fatty acid metabolism and insulin resistance.

scholarly journals FATP2 is a hepatic fatty acid transporter and peroxisomal very long-chain acyl-CoA synthetase

2010 ◽  
Vol 299 (3) ◽  
pp. E384-E393 ◽  
Author(s):  
Alaric Falcon ◽  
Holger Doege ◽  
Amy Fluitt ◽  
Bernice Tsang ◽  
Nicki Watson ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Uptake ◽  
Fatty Acid Transport ◽  
Acid Uptake ◽  
Peroxisomal Enzyme ◽  
Multifunctional Protein ◽  
Hepatic Fatty Acid ◽  
Chain Acyl ◽  
Lcfa Uptake ◽  
Long Chain

Fatty acid transport protein (FATP)2, a member of the FATP family of fatty acid uptake mediators, has independently been identified as a hepatic peroxisomal very long-chain acyl-CoA synthetase (VLACS). Here we address whether FATP2 is 1) a peroxisomal enzyme, 2) a plasma membrane-associated long-chain fatty acid (LCFA) transporter, or 3) a multifunctional protein. We found that, in mouse livers, only a minor fraction of FATP2 localizes to peroxisomes, where it contributes to approximately half of the peroxisomal VLACS activity. However, total hepatic (V)LACS activity was not significantly affected by loss of FATP2, while LCFA uptake was reduced by 40%, indicating a more prominent role in hepatic LCFA uptake. This suggests FATP2 as a potential target for a therapeutic intervention of hepatosteatosis. Adeno-associated virus 8-based short hairpin RNA expression vectors were used to achieve liver-specific FATP2 knockdown, which significantly reduced hepatosteatosis in the face of continued high-fat feeding, concomitant with improvements in liver physiology, fasting glucose, and insulin levels. Based on our findings, we propose a model in which FATP2 is a multifunctional protein that shows subcellular localization-dependent activity and is a major contributor to peroxisomal (V)LACS activity and hepatic fatty acid uptake, suggesting FATP2 as a potential novel target for the treatment of nonalcoholic fatty liver disease.

scholarly journals Rv3723/LucA coordinates fatty acid and cholesterol uptake in Mycobacterium tuberculosis

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Evgeniya V Nazarova ◽  
Christine R Montague ◽  
Thuy La ◽  
Kaley M Wilburn ◽  
Neelima Sukumar ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Mycobacterium Tuberculosis ◽  
Fatty Acid ◽  
Pathogenic Bacteria ◽  
Fatty Acid Uptake ◽  
Bacterial Virulence ◽  
Acid Uptake ◽  
Uncharacterized Protein ◽  
Fatty Acid Transporter

Pathogenic bacteria have evolved highly specialized systems to extract essential nutrients from their hosts. Mycobacterium tuberculosis (Mtb) scavenges lipids (cholesterol and fatty acids) to maintain infections in mammals but mechanisms and proteins responsible for the import of fatty acids in Mtb were previously unknown. Here, we identify and determine that the previously uncharacterized protein Rv3723/LucA, functions to integrate cholesterol and fatty acid uptake in Mtb. Rv3723/LucA interacts with subunits of the Mce1 and Mce4 complexes to coordinate the activities of these nutrient transporters by maintaining their stability. We also demonstrate that Mce1 functions as a fatty acid transporter in Mtb and determine that facilitating cholesterol and fatty acid import via Rv3723/LucA is required for full bacterial virulence in vivo. These data establish that fatty acid and cholesterol assimilation are inexorably linked in Mtb and reveals a key function for Rv3723/LucA in in coordinating thetransport of both these substrates.

scholarly journals FATP1 Is an Insulin-Sensitive Fatty Acid Transporter Involved in Diet-Induced Obesity

2006 ◽  
Vol 26 (9) ◽  
pp. 3455-3467 ◽  
Author(s):  
Qiwei Wu ◽  
Angelica M. Ortegon ◽  
Bernice Tsang ◽  
Holger Doege ◽  
Kenneth R. Feingold ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Fatty Acid ◽  
Fatty Acid Uptake ◽  
Dietary Lipids ◽  
Fatty Acid Transport ◽  
Acid Uptake ◽  
Diet Induced Obesity ◽  
Fatty Acid Transporter ◽  
Knockout Animals

ABSTRACT Fatty acid transport protein 1 (FATP1), a member of the FATP/Slc27 protein family, enhances the cellular uptake of long-chain fatty acids (LCFAs) and is expressed in several insulin-sensitive tissues. In adipocytes and skeletal muscle, FATP1 translocates from an intracellular compartment to the plasma membrane in response to insulin. Here we show that insulin-stimulated fatty acid uptake is completely abolished in FATP1-null adipocytes and greatly reduced in skeletal muscle of FATP1-knockout animals while basal LCFA uptake by both tissues was unaffected. Moreover, loss of FATP1 function altered regulation of postprandial serum LCFA, causing a redistribution of lipids from adipocyte tissue and muscle to the liver, and led to a complete protection from diet-induced obesity and insulin desensitization. This is the first in vivo evidence that insulin can regulate the uptake of LCFA by tissues via FATP1 activation and that FATPs determine the tissue distribution of dietary lipids. The strong protection against diet-induced obesity and insulin desensitization observed in FATP1-null animals suggests FATP1 as a novel antidiabetic target.

scholarly journals Hepatic fatty acid uptake is regulated by the sphingolipid acyl chain length

2014 ◽  
Vol 1841 (12) ◽  
pp. 1754-1766 ◽  
Author(s):  
Woo-Jae Park ◽  
Joo-Won Park ◽  
Alfred H. Merrill ◽  
Judith Storch ◽  
Yael Pewzner-Jung ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Chain Length ◽  
Acyl Chain ◽  
Fatty Acid Uptake ◽  
Acid Uptake ◽  
Hepatic Fatty Acid ◽  
Acyl Chain Length

scholarly journals Loss of intracellular lipid binding proteins differentially impacts saturated fatty acid uptake and nuclear targeting in mouse hepatocytes

2012 ◽  
Vol 303 (7) ◽  
pp. G837-G850 ◽  
Author(s):  
Stephen M. Storey ◽  
Avery L. McIntosh ◽  
Huan Huang ◽  
Gregory G. Martin ◽  
Kerstin K. Landrock ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Uptake ◽  
Lipid Binding ◽  
Acid Uptake ◽  
Nuclear Targeting ◽  
Fatty Acid Binding ◽  
Mouse Hepatocytes ◽  
Sterol Carrier Protein 2 ◽  
Lipid Binding Proteins ◽  
Lcfa Uptake

The liver expresses high levels of two proteins with high affinity for long-chain fatty acids (LCFAs): liver fatty acid binding protein (L-FABP) and sterol carrier protein-2 (SCP-2). Real-time confocal microscopy of cultured primary hepatocytes from gene-ablated (L-FABP, SCP-2/SCP-x, and L-FABP/SCP-2/SCP-x null) mice showed that the loss of L-FABP reduced cellular uptake of 12- N-methyl-(7-nitrobenz-2-oxa-1,3-diazo)-aminostearic acid (a fluorescent-saturated LCFA analog) by ∼50%. Importantly, nuclear targeting of the LCFA was enhanced when L-FABP was upregulated (SCP-2/SCP-x null) but was significantly reduced when L-FABP was ablated (L-FABP null), thus impacting LCFA nuclear targeting. These effects were not associated with a net decrease in expression of key membrane proteins involved in LCFA or glucose transport. Since hepatic LCFA uptake and metabolism are closely linked to glucose uptake, the effect of glucose on L-FABP-mediated LCFA uptake and nuclear targeting was examined. Increasing concentrations of glucose decreased cellular LCFA uptake and even more extensively decreased LCFA nuclear targeting. Loss of L-FABP exacerbated the decrease in LCFA nuclear targeting, while loss of SCP-2 reduced the glucose effect, resulting in enhanced LCFA nuclear targeting compared with control. Simply, ablation of L-FABP decreases LCFA uptake and even more extensively decreases its nuclear targeting.

Metabolic challenges reveal impaired fatty acid metabolism and translocation of FAT/CD36 but not FABPpm in obese Zucker rat muscle

2007 ◽  
Vol 293 (2) ◽  
pp. E566-E575 ◽  
Author(s):  
Xiao-Xia Han ◽  
Adrian Chabowski ◽  
Narendra N. Tandon ◽  
Jorge Calles-Escandon ◽  
Jan F. C. Glatz ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Acid Metabolism ◽  
Fatty Acid Uptake ◽  
Zucker Rats ◽  
Acid Oxidation ◽  
Acid Uptake ◽  
Rat Muscle ◽  
Fatty Acid Transporter ◽  
Obese Zucker Rats

We examined, in muscle of lean and obese Zucker rats, basal, insulin-induced, and contraction-induced fatty acid transporter translocation and fatty acid uptake, esterification, and oxidation. In lean rats, insulin and contraction induced the translocation of the fatty acid transporter FAT/CD36 (43 and 41%, respectively) and plasma membrane-associated fatty acid binding protein (FABPpm; 19 and 60%) and increased fatty acid uptake (63 and 40%, respectively). Insulin and contraction increased lean muscle palmitate esterification and oxidation 72 and 61%, respectively. In obese rat muscle, basal levels of sarcolemmal FAT/CD36 (+33%) and FABPpm (+14%) and fatty acid uptake (+30%) and esterification (+32%) were increased, whereas fatty acid oxidation was reduced (−28%). Insulin stimulation of obese rat muscle increased plasmalemmal FABPpm (+15%) but not plasmalemmal FAT/CD36, blunted fatty acid uptake and esterification, and failed to reduce fatty acid oxidation. In contracting obese rat muscle, the increases in fatty acid uptake and esterification and FABPpm translocation were normal, but FAT/CD36 translocation was impaired and fatty acid oxidation was blunted. There was no relationship between plasmalemmal fatty acid transporters and palmitate partitioning. In conclusion, fatty acid metabolism is impaired at several levels in muscles of obese Zucker rats; specifically, they are 1) insulin resistant with respect to FAT/CD36 translocation and fatty acid uptake, esterification, and oxidation and 2) contraction resistant with respect to fatty acid oxidation and FAT/CD36 translocation, but, conversely, 3) obese muscles are neither insulin nor contraction resistant at the level of FABPpm. Finally, 4) there is no evidence that plasmalemmal fatty acid transporters contribute to the channeling of fatty acids to specific metabolic destinations within the muscle.

scholarly journals Insulin- and leptin-regulated fatty acid uptake plays a key causal role in hepatic steatosis in mice with intact leptin signaling but not in ob/ob or db/db mice

2010 ◽  
Vol 299 (4) ◽  
pp. G855-G866 ◽  
Author(s):  
Fengxia Ge ◽  
Shengli Zhou ◽  
Chunguang Hu ◽  
Harrison Lobdell ◽  
Paul D. Berk
Keyword(s):  
Gene Expression ◽  
Fatty Acid ◽  
Hepatic Steatosis ◽  
Serum Insulin ◽  
Regulatory Element ◽  
Liver Weight ◽  
Fatty Acid Uptake ◽  
Acid Uptake ◽  
Leptin Signaling ◽  
Lcfa Uptake

Hepatic steatosis results from several processes. To assess their relative roles, hepatocellular long-chain fatty acid (LCFA) uptake was assayed in hepatocytes from C57BL/6J control mice, mice with steatosis from a high-fat diet (HFD) or 10%, 14%, or 18% ethanol (EtOH) in drinking water [functioning leptin-signaling groups (FLSGs)], and ob/ob and db/db mice. Vmax for uptake was increased vs. controls ( P < 0.001) and correlated significantly with liver weight and triglycerides (TGs) in all FLSG mice but was minimally or not increased in ob/ob and db/db mice, in which liver weights and TGs greatly exceeded projections from regressions in FLSG animals. Coefficients of determination ( R2) for these FLSG regressions suggest that increased LCFA uptake accounts for ∼80% of the increase in hepatic TGs within these groups, but increased lipogenic gene expression data suggest that enhanced LCFA synthesis is the major contributor in ob/ob and db/db. Got2, Cd36, Slc27a2, and Slc27a5 gene expression ratios were significantly upregulated in the EtOH groups, correlating with sterol regulatory element binding protein 1c ( SREBP1c) and Vmax, but only Cd36 expression was increased in HFD, ob/ob, and db/db mice. Comparison of Vmax with serum insulin and leptin suggests that both hormones contribute to upregulation of uptake in the FLSG animals. Thus, increased LCFA uptake, reflecting SREBP1c-mediated upregulation of four distinct transporters, is the dominant cause of steatosis in EtOH-fed mice. In ob/ob and db/db mice, increased LCFA synthesis appears more important. In FLSG animals, insulin upregulates hepatocellular LCFA uptake. Leptin appears to upregulate LCFA uptake or to be essential for full expression of upregulation by insulin.

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