scholarly journals The computational analyses, molecular dynamics of fatty-acid transport mechanism to the CD36 receptor

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Jihane Akachar ◽  
Catherine Etchebest ◽  
Rachid El Jaoudi ◽  
Azeddine Ibrahimi
Keyword(s):  
Molecular Dynamics ◽  
Fatty Acids ◽  
Fatty Acid ◽  
Palmitic Acid ◽  
Conformational Changes ◽  
Structural Basis ◽  
Fatty Acid Transport ◽  
Acid Uptake ◽  
Wild Type ◽  
Cavity Structure

AbstractThe transmembrane glycoprotein CD36, which is responsible of the metabolic disorders, and the elevated intake of fat induces lipid buildup, is a multifunctional scavenger receptor signaling those functions in high-affinity tissue uptake of long-chain fatty acids. In this study, we used series of molecular dynamics simulations of the wild type and mutants types K164A CD36 protein interacting with one palmitic acid (PLM) besides simulations of the wild type interacting with the three PLM to find out the mechanism of the functioning of the complex CD36/Fatty acids and the unraveling of the role of the mutation. Additionally we determined whether Lys164, mostly exposed to protein surface, played important roles in fatty acid uptake. These simulations revealed, the conformational changes induced by Lys164 residue and the altered interactions induced by the mutagenesis of surface lysine that was badly influencing the folding, utility, solubility, and stability form of the variant. Furthermore, Lys164 residue provided the structural basis of forming an opening at the region of principal portal for the dissociation of palmitic acid. The results of our simulations revealed hole two fatty acids found in CD36 cavity structure and it was the most preferred to CD36 structure stabilization.

scholarly journals The Computational Analyses, Molecular Dynamics of Fatty-Acid Transport Mechanism to the CD36 Receptor: The Outcomes of the Mutation K164A on the Binding Domain, Structure and Function

2021 ◽  
Author(s):  
Jihane Akachar ◽  
Catherine Etchebest ◽  
Rachid Eljaoudi ◽  
Azeddine Ibrahimi
Keyword(s):  
Molecular Dynamics ◽  
Fatty Acids ◽  
Fatty Acid ◽  
Palmitic Acid ◽  
Conformational Changes ◽  
Structural Basis ◽  
Fatty Acid Transport ◽  
Acid Uptake ◽  
Wild Type ◽  
Cavity Structure

Abstract The transmembrane glycoprotein CD36, which is responsible of the metabolic disorders, and the elevated intake of fat induces lipid buildup, is a multifunctional scavenger receptor signaling those functions in high-affinity tissue uptake of long-chain fatty acids. In this study, we used series of molecular dynamics simulations of the wild type and mutants types K164A CD36 protein interacting with one Palmitic acid (PLM) besides simulations of the wild type interacting with the three PLM to find out the mechanism of the functioning of the complex CD36/Fatty acids and the unraveling of the role of the mutation. Additionally we determined whether Lys164, mostly exposed to protein surface, played important roles in fatty acid uptake. These simulations revealed, the conformational changes induced by Lys164 residue and the altered interactions induced by the mutagenesis of surface lysine that was badly influencing the folding, utility, solubility, and stability form of the variant. Furthermore, Lys164 residue provided the structural basis of forming an opening at the region of principal portal for the dissociation of palmitic acid. The results of our simulations revealed hole two fatty acids found in CD36 cavity structure and it was the most preferred to CD36 structure stabilization.

scholarly journals Lipid Accumulation and Chronic Kidney Disease

Nutrients ◽  
2019 ◽  
Vol 11 (4) ◽  
pp. 722 ◽  
Author(s):  
Zhibo Gai ◽  
Tianqi Wang ◽  
Michele Visentin ◽  
Gerd Kullak-Ublick ◽  
Xianjun Fu ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Fatty Acids ◽  
Fatty Acid ◽  
Kidney Disease ◽  
Lipid Accumulation ◽  
Scavenger Receptor ◽  
Fatty Acid Uptake ◽  
Lipid Lowering ◽  
Fatty Acid Transport ◽  
Acid Uptake

Obesity and hyperlipidemia are the most prevalent independent risk factors of chronic kidney disease (CKD), suggesting that lipid accumulation in the renal parenchyma is detrimental to renal function. Non-esterified fatty acids (also known as free fatty acids, FFA) are especially harmful to the kidneys. A concerted, increased FFA uptake due to high fat diets, overexpression of fatty acid uptake systems such as the CD36 scavenger receptor and the fatty acid transport proteins, and a reduced β-oxidation rate underlie the intracellular lipid accumulation in non-adipose tissues. FFAs in excess can damage podocytes, proximal tubular epithelial cells and the tubulointerstitial tissue through various mechanisms, in particular by boosting the production of reactive oxygen species (ROS) and lipid peroxidation, promoting mitochondrial damage and tissue inflammation, which result in glomerular and tubular lesions. Not all lipids are bad for the kidneys: polyunsaturated fatty acids (PUFA) such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) seem to help lag the progression of chronic kidney disease (CKD). Lifestyle interventions, especially dietary adjustments, and lipid-lowering drugs can contribute to improve the clinical outcome of patients with CKD.

scholarly journals Additive effects of dexamethasone and palmitate on hepatic lipid accumulation and secretion

2016 ◽  
Vol 57 (4) ◽  
pp. 261-273 ◽  
Author(s):  
Ewa Harasim-Symbor ◽  
Karolina Konstantynowicz-Nowicka ◽  
Adrian Chabowski
Keyword(s):  
Liquid Chromatography ◽  
Fatty Acid ◽  
Palmitic Acid ◽  
Combined Treatment ◽  
Protective Mechanism ◽  
Gas Liquid Chromatography ◽  
Fatty Acid Transport ◽  
Acid Uptake ◽  
Additive Effects ◽  
Extracellular Lipid

Synthetic and natural glucocorticoids are able to highly modify liver lipid metabolism, which is possibly associated with nonalcoholic fatty liver disease development. We have assessed the changes in lipid and sphingolipid contents in hepatocytes, lipid composition and saturation status as well as the expression of proteins involved in fatty acid transport after both dexamethasone and palmitate treatments. The experiments were conducted on primary rat hepatocytes, incubated with dexamethasone and/or palmitic acid during short (16 h) and prolonged (40 h) exposure. Intracellular and extracellular lipid and sphingolipid contents were assessed by gas liquid chromatography and high-performance liquid chromatography, respectively. The expression of selected proteins was estimated by Western blotting. Short and prolonged exposure to dexamethasone combined with palmitic acid resulted in increased expression of fatty acid transporters, which was subsequently reflected by excessive intracellular accumulation of triacylglycerols and ceramide. The expression of microsomal transfer protein and cassette transporter was also significantly increased after dexamethasone and palmitate treatment, which was in accordance with elevated extracellular lipid and sphingolipid contents. Our data showed additive effects of dexamethasone and palmitate on protein-dependent fatty acid uptake in primary hepatocytes, resulting in the increased accumulation of triacylglycerols and sphingolipids. Moreover, the combined treatment altered fatty acid composition and diminished triacylglycerols desaturation index. Importantly, we observed that additive effects on both increased microsomal transport protein expression as well as elevated export of triacylglycerols, which may be relevant as a liver protective mechanism.

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.

Palmitic acid uptake by the rat soleus muscle in vitro

2001 ◽  
Vol 79 (4) ◽  
pp. 419-424 ◽  
Author(s):  
M Górecka ◽  
M Synak ◽  
L Budohoski ◽  
J Langfort ◽  
S Moskalewski ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Fatty Acid ◽  
Palmitic Acid ◽  
Soleus Muscle ◽  
Fatty Acid Uptake ◽  
Cellular Fatty Acid ◽  
Acid Uptake ◽  
Acid Complex ◽  
Rat Soleus Muscle

The rate of fatty acid uptake, oxidation, and deposition in skeletal muscles in relation to total and unbound to albumin fatty acids concentration in the medium were investigated in the incubated rat soleus muscle. An immunohistochemical technique was applied to demonstrate whether the albumin-bound fatty acid complex from the medium penetrates well within all areas of the muscle strips. It was found that the percentage of incorporation of palmitic acid into intramuscular lipids was fairly constant, independently of the fatty acid concentration in the medium, and amounted to 63–72% for triacylglycerols, 7–12% for diacylglycerols-monoacylglycerols, and 19–26% for phospholipids. Both palmitic acid incorporation into the muscle triacylglycerol stores and its oxidation to CO2closely correlated with an increase in both total and unbound to albumin fatty acid concentrations in the incubation medium. Under conditions of increased total but constant unbound to albumin palmitic acid concentrations, the incorporation of palmitic acid into triacylglycerols and its oxidation to CO2were also increased, but to a lower extent. This supports the hypothesis that the cellular fatty acid metabolism depends not only on the availability of fatty acids unbound to albumin, but also on the availability of fatty acids complexed to albumin.Key words: skeletal muscle, fatty acids, triacylglycerols, phospholipids.

Studies on the uptake of fatty acids by brush border membranes of the rabbit intestine

1985 ◽  
Vol 63 (4) ◽  
pp. 249-256 ◽  
Author(s):  
P. Proulx ◽  
H. Aubry ◽  
I. Brglez ◽  
D. G. Williamson
Keyword(s):  
Fatty Acids ◽  
Oleic Acid ◽  
Fatty Acid ◽  
Palmitic Acid ◽  
Bile Salt ◽  
Chain Length ◽  
Brush Border ◽  
Fatty Acid Uptake ◽  
Acid Uptake ◽  
Egg Lecithin

Initial studies revealed that the uptake of palmitic acid and oleic acid into brush border membranes was similar when these were isolated from either whole small intestine, jejunum, or ileum. The uptake of these fatty acids was somewhat lower with membranes obtained from duodenum. Subsequent studies, all with membranes obtained from whole intestine, indicated an increase in binding with chain length of fatty acid of up to 16 carbons. Unsaturation decreased this uptake somewhat. Taurocholate and 1-palmitoyl lysolecithin had a moderate stimulatory effect on the binding of oleic acid and palmitic acid at concentrations of 10 and 0.5 mM, respectively, and inhibited at higher concentrations. Addition of 1.4 mM egg lecithin to the fatty acid – bile salt micelles, such that the lecithin – bile salt ratio was 0.2, decreased the uptake of fatty acids generally, but did not significantly affect the pattern of binding by membrane fractions isolated from different segments nor did it change the pattern of labelling when fatty acid chain length and unsaturation were varied. At lower concentrations, egg lecithin had little effect on the uptake of oleic acid, whereas dipalmitoyl phosphatidylcholine stimulated binding of both palmitic acid and oleic acid over the entire range of concentrations tested. Preincubation of the membranes with this saturated phospholipid stimulated the uptake of oleic acid, and addition of this choline lipid to the oleic acid – bile salt containing micelles did not substantially enhance fatty acid uptake in lipid-treated membranes. The binding of fatty acid was very rapid either in the presence or the absence of Ca2+, such that even in zero-time controls essentially equilibrium bindings were obtained. The presence of Ca2+ stimulated the incorporation substantially. The results as a whole indicate that fatty acid uptake into brush border membrane is very responsive to a variety of conditions which could prevail in the gut during the absorption process.

Fatty acid transport and metabolism in HepG2 cells

2006 ◽  
Vol 290 (3) ◽  
pp. G528-G534 ◽  
Author(s):  
Wen Guo ◽  
Nasi Huang ◽  
Jun Cai ◽  
Weisheng Xie ◽  
James A. Hamilton
Keyword(s):  
Fatty Acids ◽  
Plasma Membrane ◽  
Fatty Acid ◽  
Hepg2 Cells ◽  
Fatty Acid Uptake ◽  
Metabolic Inhibitors ◽  
Fatty Acid Transport ◽  
Acid Uptake ◽  
Triacsin C ◽  
Membrane Bound

The mechanism(s) of fatty acid uptake by liver cells is not fully understood. We applied new approaches to address long-standing controversies of fatty acid uptake and to distinguish diffusion and protein-based mechanisms. Using HepG2 cells containing an entrapped pH-sensing fluorescence dye, we showed that the addition of oleate (unbound or bound to cyclodextrin) to the external buffer caused a rapid (seconds) and dose-dependent decrease in intracellular pH (pHin), indicating diffusion of fatty acids across the plasma membrane. pHin returned to its initial value with a time course (in min) that paralleled the metabolism of radiolabeled oleate. Preincubation of cells with the inhibitors phloretin or triacsin C had no effect on the rapid pHin drop after the addition of oleate but greatly suppressed pHin recovery. Using radiolabeled oleate, we showed that its esterification was almost completely inhibited by phloretin or triacsin C, supporting the correlation between pHin recovery and metabolism. We then used a dual-fluorescence assay to study the interaction between HepG2 cells and cis-parinaric acid (PA), a naturally fluorescent but slowly metabolized fatty acid. The fluorescence of PA increased rapidly upon its addition to cells, indicating rapid binding to the plasma membrane; pHin decreased rapidly and simultaneously but did not recover within 5 min. Phloretin had no effect on the PA-mediated pHin drop or its slow recovery but decreased the absolute fluorescence of membrane-bound PA. Our results show that natural fatty acids rapidly bind to, and diffuse through, the plasma membrane without hindrance by metabolic inhibitors or by an inhibitor of putative membrane-bound fatty acid transporters.

scholarly journals Insulin-stimulated adipocytes secrete lactate to promote endothelial fatty acid uptake and transport

2021 ◽  
Author(s):  
Ayon Ibrahim ◽  
Michael D. Neinast ◽  
Kristina Li ◽  
Michael Noji ◽  
Boa Kim ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Endothelial Cells ◽  
Fatty Acid ◽  
Lactate Concentration ◽  
Lactate Production ◽  
Fatty Acid Uptake ◽  
Endothelial Barrier ◽  
Fatty Acid Transport ◽  
Acid Uptake ◽  
Uptake And Transport

Insulin stimulates adipose tissue to extract fatty acids from circulation and sequester them inside adipose cells. How fatty acids are transported across the capillary endothelial barrier, or how this process is regulated, remains unclear. We modeled the relationship of adipocytes and endothelial cells in vitro to test the role of insulin in fatty acid transport. Treatment of endothelial cells with insulin did not affect endothelial fatty acid uptake, but endothelial cells took up more fatty acids when exposed to media conditioned by adipocytes treated with insulin. Manipulations of this conditioned media indicated that the secreted factor is a small, hydrophilic, non-proteinaceous metabolite. Factor activity was correlated with lactate concentration, and inhibition of lactate production in adipocytes abolished the activity. Finally, lactate alone was sufficient to increase endothelial uptake of both free fatty acids and lipids liberated from chylomicrons, and to promote trans-endothelial transport, at physiologically relevant concentrations. Together, these data suggest that insulin drives adipocytes to secrete lactate, which then acts in a paracrine fashion to promote fatty acid uptake and transport across the neighboring endothelial barrier.

A STUDY ON CLASSIFICATION OF INHIBITORS OF FATTY ACID TRANSPORT PROTEIN-2 IN CELL

2021 ◽  
pp. 58-60
Author(s):  
Anand Shanker Singh ◽  
G . Radhika ◽  
R . Praveen Kumar ◽  
Debarshi Jana
Keyword(s):  
Fatty Acids ◽  
Fatty Acid ◽  
High Throughput ◽  
Hepg2 Cells ◽  
High Throughput Screening ◽  
Atypical Antipsychotics ◽  
Fatty Acid Uptake ◽  
Fatty Acid Transport ◽  
Acid Uptake ◽  
Acid Transport

Inhibition of uptake of fatty acids in non-adipose tissues seems an attractive mechanism for treatment of lipotoxicity, dyslipidemia and other elements related to metabolic syndrome and obesity. Fatty acid transport proteins (FATPs) are bifunctional proteins involved in the uptake and activation of fatty acids by esterication with coenzyme A. To date, only inhibitors specic to FATP1 and FATP4 have been identied. Here we characterize a FATP2-specic fatty acid uptake inhibitor, CB5. Identied in a high throughput screening in yeast transformed with humanFATP2, CB5 is effective in inhibiting the uptake of fatty acid at low micro-molar ranges in cell lines that are models for intestines, liver, muscle, pancreas and adipose tissue with varying potencies. Inhibition was also specic for long and very-long chain fatty acids and not for medium chain fatty acids, which are transported by diffusion. Finally, CB5 was effective in protecting the cell lines that are models for liver and pancreas and primary liver cells from lipotoxic effects of saturated fatty acid, palmitic acid. High throughput screening also identied clozapine and chlorpromazine, atypical antipsychotics drugs, as inhibitors of FATP2-mediated fatty acid uptake in yeast system. However, atypical antipsychotics were ineffective in inhibiting the uptake of FAanalog C1-BODIPY-C12 in HepG2 cells. They were also ineffective in protecting HepG2 cells from the lipotoxic effects generated by saturated fatty acid compared to CB5 that exhibited protection to the cells, demonstrating that they are not effective inhibitors of fatty acid transport compared with CB5.

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