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

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

AbstractPathogenic bacteria have evolved highly specialized systems to extract essential nutrients from their hosts andMycobacterium tuberculosis(Mtb) scavenges lipids (cholesterol and fatty acids) to maintain infection in mammals. While the uptake of cholesterol by Mtb is mediated by the Mce4 transporter, the route(s) of uptake of fatty acids remain unknown. Here, we demonstrate that an uncharacterized protein LucA, integrates the assimilation of both cholesterol and fatty acids in Mtb. LucA interacts with subunits of the Mce1 and Mce4 complexes to coordinate the activities of these nutrient transporters. We also demonstrate that Mce1 functions as an important fatty acid transporter in Mtb and we determine that the integration of cholesterol and fatty acid transport by LucA is required for full bacterial virulencein vivo. These data establish that fatty acid and cholesterol assimilation are inexorably linked in Mtb and reveals a key role for LucA in coordinating both transport activities.

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.

Effect of surface and intracellular pH on hepatocellular fatty acid uptake

1996 ◽  
Vol 271 (6) ◽  
pp. G1067-G1073
Author(s):  
C. Elsing ◽  
A. Kassner ◽  
W. Stremmel
Keyword(s):  
Fatty Acids ◽  
Plasma Membrane ◽  
Fatty Acid ◽  
Intracellular Ph ◽  
Outer Surface ◽  
Fatty Acid Uptake ◽  
Proton Gradient ◽  
Fatty Acid Transport ◽  
Acid Uptake ◽  
Acid Transport

Fatty acids enter hepatocytes, at least in part, by a carrier-mediated uptake mechanism. The importance of driving forces for fatty acid uptake is still controversial. To evaluate possible driving mechanisms for fatty acid transport across plasma membranes, we examined the role of transmembrane proton gradients on fatty acid influx in primary cultured rat hepatocytes. After hepatocytes were loaded with SNARF-1 acetoxymethyl ester, changes in intracellular pH (pHi) under different experimental conditions were measured and recorded by confocal laser scanning microscopy. Fatty acid transport was increased by 45% during cellular alkalosis, achieved by adding 20 mM NH4Cl to the medium, and a concomitant paracellular acidification was observed. Fatty acid uptake was decreased by 30% during cellular acidosis after withdrawal of NH4Cl from the medium. Cellular acidosis activates the Na+/H+ antiporter to export excessive protons to the outer cell surface. Inhibition of Na+/H+ antiporter activity by amiloride diminishes pHi recovery and thereby accumulation of protons at the outer surface of the plasma membrane. Under these conditions, fatty acid uptake was further inhibited by 57% of control conditions. This suggests stimulation of fatty acid influx by an inwardly directed proton gradient. The accelerating effect of protons at the outer surface of the plasma membrane was confirmed by studies in which pH of the medium was varied at constant pHi. Significantly higher fatty acid influx rates were observed at low buffer pH. Recorded differences in fatty acid uptake appeared to be independent of changes in membrane potential, because BaCl2 did not influence initial uptake velocity during cellular alkalosis and paracellular acidosis. Moreover, addition of oleate-albumin mixtures to the NH4Cl incubation buffer did not change the observed intracellular alkalinization. In contrast, after cells were acid loaded, addition of oleate-albumin solutions to the recovery buffer increased pHi recovery rates from 0.21 +/- 0.02 to 0.36 +/- 0.05 pH units/min (P < 0.05), indicating that fatty acids further stimulate Na+/H+ antiporter activity during pHi recovery from an acid load. It is concluded that carrier-mediated uptake of fatty acids in hepatocytes follows an inwardly directed transmembrane proton gradient and is stimulated by the presence of H+ at the outer surface of the plasma membrane.

scholarly journals High Membranous Expression of Fatty Acid Transport Protein 4 Is Associated with Tumorigenesis and Tumor Progression in Clear Cell Renal Cell Carcinoma

2019 ◽  
Vol 2019 ◽  
pp. 1-7 ◽  
Author(s):  
Young-Sik Kim ◽  
Jiyoon Jung ◽  
Hoiseon Jeong ◽  
Ju-Han Lee ◽  
Hwa Eun Oh ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Renal Cell Carcinoma ◽  
Fatty Acid ◽  
Tumor Cells ◽  
Clear Cell ◽  
Female Gender ◽  
Fatty Acid Transport ◽  
Acid Transport ◽  
Cell Renal Cell Carcinoma ◽  
Normal Cells

The increased requirement of fatty acids forces cancer cells to enhance uptake of fatty acids from the extracellular milieu, in addition to de novo lipogenesis. Coexpression of cluster of differentiation 36 (CD36) with fatty acid transport protein 4 (FATP4) or long-chain acyl CoA synthetase 1 (ACSL1) synergistically activated fatty acid uptake in experimental models. In this study, we investigated the immunohistochemical expression of CD36, FATP4, and ACSL1 in 180 cases of clear cell renal cell carcinoma (RCC) in comparison with 80 specimens of the normal kidney. We also examined the clinical implication of these three fatty acid transporters in RCC, which was validated by an open-access The Cancer Genome Atlas data analysis. Both CD36 and FATP4 revealed higher membranous expressions in RCC tumor cells than in normal cells. In contrast, ACSL1 expression was remarkably reduced in RCC tumor cells compared to normal cells. CD36, FATP4, and ACSL1 showed high expressions in 74 (41.1%), 85 (47.2%), and 72 (40.0%) out of 180 RCC cases, respectively. Clinically, high FATP4 in tumor cells was associated with female gender (p=0.05), high TNM stage (p=0.039), tumor necrosis (p=0.009), and tumor recurrence (p=0.037), while high ACSL1 was only related to female gender (p=0.023). CD36 expression revealed no correlation with the clinicopathologic parameters of RCC. Increased FATP4 expression displayed an association with short recurrence-free survival (p=0.003). In conclusion, the high FATP4 expression was clinically associated with poor prognostic factors of RCC. Overexpression of membranous FATP4 and CD36 combined with reduced cytoplasmic expression of ACSL1 might be a tumor-specific feature of RCC, contributing to the tumorigenesis and tumor progression.

scholarly journals Ligand-Activated Peroxisome Proliferator Activated Receptor γ Alters Placental Morphology and Placental Fatty Acid Uptake in Mice

Endocrinology ◽  
2007 ◽  
Vol 148 (8) ◽  
pp. 3625-3634 ◽  
Author(s):  
W. Timothy Schaiff ◽  
F. F. (Russ) Knapp ◽  
Yaacov Barak ◽  
Tal Biron-Shental ◽  
D. Michael Nelson ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Transport ◽  
Peroxisome Proliferator ◽  
Acid Uptake ◽  
Acid Transport ◽  
Placental Development ◽  
Peroxisome Proliferator Activated Receptor ◽  
Altered Expression ◽  
Pparγ Agonist

The nuclear receptor peroxisome proliferator activated receptor γ (PPARγ) is essential for murine placental development. We previously showed that activation of PPARγ in primary human trophoblasts enhances the uptake of fatty acids and alters the expression of several proteins associated with fatty acid trafficking. In this study we examined the effect of ligand-activated PPARγ on placental development and transplacental fatty acid transport in wild-type (wt) and PPARγ+/− embryos. We found that exposure of pregnant mice to the PPARγ agonist rosiglitazone for 8 d (embryonic d 10.5–18.5) reduced the weights of wt, but not PPARγ+/− placentas and embryos. Exposure to rosiglitazone reduced the thickness of the spongiotrophoblast layer and the surface area of labyrinthine vasculature, and altered expression of proteins implicated in placental development. The expression of fatty acid transport protein 1 (FATP1), FATP4, adipose differentiation related protein, S3-12, and myocardial lipid droplet protein was enhanced in placentas of rosiglitazone-treated wt embryos, whereas the expression of FATP-2, -3, and -6 was decreased. Additionally, rosiglitazone treatment was associated with enhanced accumulation of the fatty acid analog 15-(p-iodophenyl)-3-(R, S)-methyl pentadecanoic acid in the placenta, but not in the embryos. These results demonstrate that in vivo activation of PPARγ modulates placental morphology and fatty acid accumulation.

Stopped-flow kinetic analysis of long-chain fatty acid dissociation from bovine serum albumin

2002 ◽  
Vol 363 (3) ◽  
pp. 809-815 ◽  
Author(s):  
Erland J.F. DEMANT ◽  
Gary V. RICHIERI ◽  
Alan M. KLEINFELD
Keyword(s):  
Fatty Acids ◽  
Fatty Acid ◽  
Time Course ◽  
Acid Dissociation ◽  
Fatty Acid Transport ◽  
Acid Transport ◽  
Fatty Acid Binding ◽  
Kinetics Of ◽  
Initial Fatty Acid ◽  
Long Chain

The kinetics of the interaction of long-chain fatty acids (referred to as fatty acids) with albumin is critical to understanding the role of albumin in fatty acid transport. In this study we have determined the kinetics of fatty acid dissociation from BSA and the BSA-related fatty acid probe BSA-HCA (BSA labelled with 7-hydroxycoumarin-4-acetic acid) by stopped-flow methods. Fatty acid—albumin complexes of a range of natural fatty acid types and albumin molecules (donors) were mixed with three fatty acid-binding acceptor proteins. Dissociation of fatty acids from the donor was monitored by either the time course of donor fluorescence/absorbance or the time course of acceptor fluorescence. The results of these measurements indicate that fatty acid dissociation from BSA as well as BSA-HCA is well described by a single exponential function over the entire range of fatty acid/albumin molar ratios used in these measurements, from 0.5:1 to 6:1. The observed rate constants (kobs) for the dissociation of each fatty acid type reveal little or no dependence on the initial fatty acid/albumin ratio. However, dissociation rates were dependent upon the type of fatty acid. In the case of native BSA with an initial fatty acid/BSA molar ratio of 3:1, the order of kobs values was stearic acid (1.5s−1)<oleic acid<palmitic acid≅linoleic acid<arachidonic acid (8s−1) at 37°C. The corresponding values for BSA-HCA were about half the values for BSA. The results of this study show that the rate of fatty acid dissociation from native BSA is more than 10-fold faster than reported previously and that the off-rate constants for the five primary fatty acid-binding sites differ by less than a factor of 2. We conclude that for reported rates of fatty acid transport across cell membranes, dissociation of fatty acids from the fatty acid—BSA complexes used in the transport studies should not be rate-limiting.

scholarly journals Fatty acid transport proteins: targeting FATP2 as a gatekeeper involved in the transport of exogenous fatty acids

MedChemComm ◽  
2016 ◽  
Vol 7 (4) ◽  
pp. 612-622 ◽  
Author(s):  
Paul N. Black ◽  
Constance Ahowesso ◽  
David Montefusco ◽  
Nipun Saini ◽  
Concetta C. DiRusso
Keyword(s):  
Fatty Acids ◽  
Fatty Acid ◽  
Fatty Acid Metabolism ◽  
Acid Metabolism ◽  
Transport Proteins ◽  
Fatty Acid Transport ◽  
Acid Transport ◽  
Fatty Acid Transport Proteins

FATP2 as the gatekeeper (A), dysregulation of fatty acid metabolism from FA overload (B), and Lipofermata or Grassofermata treatment (C).

Hypoxia-induced fatty acid transporter translocation increases fatty acid transport and contributes to lipid accumulation in the heart

FEBS Letters ◽  
2006 ◽  
Vol 580 (15) ◽  
pp. 3617-3623 ◽  
Author(s):  
Adrian Chabowski ◽  
Jan Górski ◽  
Jorge Calles-Escandon ◽  
Narendra N. Tandon ◽  
Arend Bonen
Keyword(s):  
Fatty Acid ◽  
Lipid Accumulation ◽  
Fatty Acid Transport ◽  
Acid Transport ◽  
Fatty Acid Transporter ◽  
Acid Transporter
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