Structure-dependent effects of pyridine derivatives on mechanisms of intestinal fatty acid uptake: regulation of nicotinic acid receptor and fatty acid transporter expression

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.

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Fatty acid transporter expression and regulation is impaired in placental macrovascular endothelial cells in obese women

The Journal of Maternal-Fetal & Neonatal Medicine ◽

10.1080/14767058.2017.1397119 ◽

2017 ◽

Vol 32 (6) ◽

pp. 971-978 ◽

Cited By ~ 2

Author(s):

Xiaohua Yang ◽

Patricia Glazebrook ◽

Geraldine C. Ranasinghe ◽

Maricela Haghiac ◽

Virtu Calabuig-Navarro ◽

...

Keyword(s):

Endothelial Cells ◽

Fatty Acid ◽

Obese Women ◽

Fatty Acid Transporter ◽

Acid Transporter ◽

Transporter Expression

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Changes in the Diaphragm Lipid Content after Administration of Streptozotocin and High-Fat Diet Regime

Journal of Diabetes Research ◽

10.1155/2017/3437169 ◽

2017 ◽

Vol 2017 ◽

pp. 1-12 ◽

Cited By ~ 3

Author(s):

Bartlomiej Lukaszuk ◽

Agnieszka Miklosz ◽

Malgorzata Zendzian-Piotrowska ◽

Beata Wojcik ◽

Jan Gorski ◽

...

Keyword(s):

Insulin Resistance ◽

Fatty Acid ◽

High Fat Diet ◽

High Fat ◽

Ceramide Synthesis ◽

Male Wistar Rats ◽

Fatty Acid Transporter ◽

Acid Transporter ◽

Fatty Acid Species ◽

Transporter Expression

The diaphragm is a dome-shaped skeletal muscle indispensable for breathing. Its activity contributes up to 70% of the total ventilatory function at rest. In comparison to other skeletal muscles, it is distinguished by an oxidative phenotype and uninterrupted cyclic contraction pattern. Surprisingly, the research regarding diaphragm diabetic phenotype particularly in the light of lipid-induced insulin resistance is virtually nonexistent. Male Wistar rats were randomly allocated into 3 groups: control, streptozotocin-induced (STZ) type-1 diabetes, and rodents fed with high-fat diet (HFD). Additionally, half of the animals from each group were administered with myriocin, a robust, selective inhibitor of ceramide synthesis and, therefore, a potent agent ameliorating insulin resistance. Diaphragm lipid contents were evaluated using chromatography. Fatty acid transporter expression was determined by Western blot. The STZ and HFD rats had increased concentration of lipids, namely, ceramides (CER) and diacylglycerols (DAG). Interestingly, this coincided with an increased concentration of long-chain (C ≥ 16) saturated fatty acid species present in both the aforementioned lipid fractions. The CER/DAG accumulation was accompanied by an elevated fatty acid transporter expression (FATP-1 in HFD and FATP-4 in STZ). Surprisingly, we observed a significantly decreased triacylglycerol content in the diaphragms of STZ-treated rats.

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

eLife ◽

10.7554/elife.26969 ◽

2017 ◽

Vol 6 ◽

Cited By ~ 50

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.

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

Molecular and Cellular Biology ◽

10.1128/mcb.26.9.3455-3467.2006 ◽

2006 ◽

Vol 26 (9) ◽

pp. 3455-3467 ◽

Cited By ~ 172

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.

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Fatty acid transporter expression is decreased in placental macrovascular endothelial cells, but not trophoblasts, in obese women

Placenta ◽

10.1016/j.placenta.2016.06.245 ◽

2016 ◽

Vol 45 ◽

pp. 132

Author(s):

Xiaohua Yang ◽

Patricia Glazebrook ◽

Maricela Haghiac ◽

Judi Minium ◽

Sylvie Hauguel deMouzon ◽

...

Keyword(s):

Endothelial Cells ◽

Fatty Acid ◽

Obese Women ◽

Fatty Acid Transporter ◽

Acid Transporter ◽

Transporter Expression

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Developmental Accretion of Docosahexaenoic Acid Is Independent of Fatty Acid Transporter Expression in Brain and Lung Tissues of C57BL/6 and Fat1 Mice

Journal of Nutrition ◽

10.1093/jn/nxz074 ◽

2019 ◽

Vol 149 (10) ◽

pp. 1724-1731 ◽

Cited By ~ 2

Author(s):

William Yakah ◽

Pratibha Singh ◽

George Perides ◽

Joanne Brown ◽

Steven D Freedman ◽

...

Keyword(s):

Fatty Acid ◽

Docosahexaenoic Acid ◽

Corn Oil ◽

Postnatal Period ◽

Developmental Expression ◽

Developmentally Regulated ◽

Tissue Specific ◽

Fatty Acid Transporter ◽

Acid Transporter ◽

Transporter Expression

ABSTRACT Background Developmental expression of fatty acid transporters and their role in polyunsaturated fatty acid concentrations in the postnatal period have not been evaluated. Objective We hypothesized that transporter expression is developmentally regulated, tissue-specific, and that expression can modulate fatty acid accretion independently of diet. Methods Brain and lung transporter expression were quantified in C57BL/6 wild-type (WT) and Fat1 mice. Pups were dam-fed until day 21. Dams were fed AIN-76A 10% corn oil to represent a typical North American/European diet. After weaning, mice were fed the same diet as dams. Gene expression of Fatp1, Fatp4, Fabp5, and Fat/cd36 was quantified by quantitative reverse transcriptase-polymerase chain reaction. Fatty acid concentrations were measured by GC–MS. Results Brain docosahexaenoic acid (DHA) concentrations increased from day 3 to day 28 in both genotypes, with higher concentrations at days 3 and 14 in Fat1 than in WT mice [median (IQR)]: 10.7 (10.6–11.2) mol% compared with 6.6 (6.4–7.2) mol% and 12.5 (12.4–12.9) mol% compared with 8.9 (8.7–9.1) mol%, respectively; P < 0.05). During DHA accrual, transporter expression decreased. Fold changes in brain Fatp4, Fabp5, and Fat/cd36 were inversely correlated with fold changes in brain DHA concentrations in Fat1 relative to WT mice (ρ = −0.85, −0.75, and −0.78, respectively; P ≤ 0.001). Lung DHA concentrations were unchanged across the 3 time points for both genotypes. Despite unchanging DHA concentrations, there was increased expression of Fatp1 at days 14 and 28 (5-fold), Fatp4 at day 14 (2.3-fold), and Fabp5 at day 14 (3.8-fold) relative to day 3 in Fat1 mice. In WT mice, Fatp1 increased almost 5-fold at day 28 relative to day 3. There was no correlation between lung transporters and DHA concentrations in Fat1 relative to WT mice. Conclusions Development of fatty acid transporter expression in C57BL/6 WT and Fat1 mice is genotype and tissue specific. Further, postnatal accretion of brain DHA appears independent of transporter status, with tissue concentrations representing dietary contributions.

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

Circulation Research ◽

10.1161/res.117.suppl_1.233 ◽

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.

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

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00106.2007 ◽

2007 ◽

Vol 293 (2) ◽

pp. E566-E575 ◽

Cited By ~ 52

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.

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Fatty acid transporter expression in human myocytes

The FASEB Journal ◽

10.1096/fasebj.22.1_supplement.936.12 ◽

2008 ◽

Vol 22 (S1) ◽

Author(s):

Jill A Bell ◽

Melissa A Reed ◽

Deborah M Muoio ◽

G. Lynis Dohm

Keyword(s):

Fatty Acid ◽

Fatty Acid Transporter ◽

Acid Transporter ◽

Transporter Expression

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