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.

scholarly journals Endogenous Peroxisome Proliferator-Activated Receptor-γ Augments Fatty Acid Uptake in Oxidative Muscle

Endocrinology ◽  
2008 ◽  
Vol 149 (11) ◽  
pp. 5374-5383 ◽  
Author(s):  
Andrew W. Norris ◽  
Michael F. Hirshman ◽  
Jianrong Yao ◽  
Niels Jessen ◽  
Nicolas Musi ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Uptake ◽  
Transport Protein ◽  
Fatty Acid Transport ◽  
Peroxisome Proliferator ◽  
Acid Uptake ◽  
Acid Transport ◽  
Peroxisome Proliferator Activated Receptor ◽  
Nonesterified Fatty Acids ◽  
Fatty Acid Transport Protein

In the setting of insulin resistance, agonists of peroxisome proliferator-activated receptor (PPAR)-γ restore insulin action in muscle and promote lipid redistribution. Mice with muscle-specific knockout of PPARγ (MuPPARγKO) develop excess adiposity, despite reduced food intake and normal glucose disposal in muscle. To understand the relation between muscle PPARγ and lipid accumulation, we studied the fuel energetics of MuPPARγKO mice. Compared with controls, MuPPARγKO mice exhibited significantly increased ambulatory activity, muscle mitochondrial uncoupling, and respiratory quotient. Fitting with this latter finding, MuPPARγKO animals compared with control siblings exhibited a 25% reduction in the uptake of the fatty acid tracer 2-bromo-palmitate (P < 0.05) and a 13% increase in serum nonesterified fatty acids (P = 0.05). These abnormalities were associated with no change in AMP kinase (AMPK) phosphorylation, AMPK activity, or phosphorylation of acetyl-CoA carboxylase in muscle and occurred despite increased expression of fatty acid transport protein 1. Palmitate oxidation was not significantly altered in MuPPARγKO mice despite the increased expression of several genes promoting lipid oxidation. These data demonstrate that PPARγ, even in the absence of exogenous activators, is required for normal rates of fatty acid uptake in oxidative skeletal muscle via mechanisms independent of AMPK and fatty acid transport protein 1. Thus, when PPARγ activity in muscle is absent or reduced, there will be decreased fatty acid disposal leading to diminished energy utilization and ultimately adiposity.

scholarly journals De novo fatty acid synthesis by Schwann cells is essential for peripheral nervous system myelination

2018 ◽  
Vol 217 (4) ◽  
pp. 1353-1368 ◽  
Author(s):  
Laura Montani ◽  
Jorge A. Pereira ◽  
Camilla Norrmén ◽  
Hartmut B.F. Pohl ◽  
Elisa Tinelli ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Synthase ◽  
De Novo ◽  
Ex Vivo ◽  
Intrinsic Activity ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Endogenous Fatty Acid ◽  
Pparγ Agonist

Myelination calls for a remarkable surge in cell metabolism to facilitate lipid and membrane production. Endogenous fatty acid (FA) synthesis represents a potentially critical process in myelinating glia. Using genetically modified mice, we show that Schwann cell (SC) intrinsic activity of the enzyme essential for de novo FA synthesis, fatty acid synthase (FASN), is crucial for precise lipid composition of peripheral nerves and fundamental for the correct onset of myelination and proper myelin growth. Upon FASN depletion in SCs, epineurial adipocytes undergo lipolysis, suggestive of a compensatory role. Mechanistically, we found that a lack of FASN in SCs leads to an impairment of the peroxisome proliferator-activated receptor (PPAR) γ–regulated transcriptional program. In agreement, defects in myelination of FASN-deficient SCs could be ameliorated by treatment with the PPARγ agonist rosiglitazone ex vivo and in vivo. Our results reveal that FASN-driven de novo FA synthesis in SCs is mandatory for myelination and identify lipogenic activation of the PPARγ transcriptional network as a putative downstream functional mediator.

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 Regulation of cardiac fatty acids metabolism in transgenic mice overexpressing bovine GH

2009 ◽  
Vol 201 (3) ◽  
pp. 419-427 ◽  
Author(s):  
Fausto Bogazzi ◽  
Francesco Raggi ◽  
Federica Ultimieri ◽  
Dania Russo ◽  
Aldo D'Alessio ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Transgenic Mice ◽  
Fatty Acid Transport ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Fatty Acid Binding ◽  
Chain Acyl ◽  
Fatty Acids Metabolism ◽  
Key Enzyme ◽  
Key Steps

Cardiac energy metabolism depends mainly on fatty acid (FA) oxidation; however, regulation of FA metabolism in acromegalic (Acro) heart is unknown. The aim of the study was to evaluate cardiac expression of key proteins of FA metabolism in young and elder transgenic mice overexpressing bovine GH Acro. Expression of proteins regulating FA entry into the cells, their uptake by mitochondria and β-oxidation were evaluated by western blot, while FA content by Fourier transform infrared microspectrometry. Regulatory mechanisms of key steps of FA metabolism were also studied. The expression of plasma-membrane FA carriers (fatty acid-binding protein and fatty acid transport protein-1) and acylCoA synthetase was higher in young and lower in elder Acro than in corresponding controls; likewise, expression of cytoplasm to mitochondria-1 (CPT-1), the key enzyme of mitochondrial FA uptake, and that of medium-chain acyl-CoA dehydrogenase and long-chain acyl-CoA dehydrogenase, two regulatory β-oxidation dehydrogenases, followed a similar pattern. FA content was lower in young and higher in elder Acro than in wild-type, suggesting an increased utilisation in young animals. GH regulated expression of key proteins of FA metabolism through changes in peroxisome proliferator-activated receptor α (PPARα) expression, which varied accordingly. GH effect was confirmed by treatment of Acro mice with a receptor antagonist, which abolished changes in key proteins of FA metabolism in young Acro. GH increased phosphorylation of AMP-activated protein kinase and anti-acetyl-CoA-carboxylase, two regulatory kinases, leading to lower CPT-1 inhibition by malonyl-CoA, and intervened in regulating PPARα expression through the ERK 1/2 pathway. In conclusion, chronic GH excess increased FA metabolism in the young age, whereas its action was overwhelmed in elder ages likely by GH-independent mechanisms, leading to reduced expression of key enzyme of FA metabolism.

Protein-Mediated Fatty Acid Uptake: Novel Insights from In Vivo Models

Physiology ◽  
2006 ◽  
Vol 21 (4) ◽  
pp. 259-268 ◽  
Author(s):  
Holger Doege ◽  
Andreas Stahl
Keyword(s):  
Fatty Acid ◽  
Energy Homeostasis ◽  
Fatty Acid Uptake ◽  
Cellular Fatty Acid ◽  
Fatty Acid Transport ◽  
Acid Uptake ◽  
In Vivo Models ◽  
Knockout Animal ◽  
Fatty Acid Transport Proteins

Long-chain fatty acids are both important metabolites as well as signaling molecules. Fatty acid transport proteins are key mediators of cellular fatty acid uptake and recent transgenic and knockout animal models have provided new insights into their contribution to energy homeostasis and to pathological processes, including obesity and insulin desensitization.

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 Structural basis of altered potency and efficacy displayed by a major in vivo metabolite of the anti-diabetic PPARγ drug pioglitazone

2018 ◽  
Author(s):  
Sarah A. Mosure ◽  
Jinsai Shang ◽  
Richard Brust ◽  
Jie Zheng ◽  
Patrick R. Griffin ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Activation Function ◽  
Structural Basis ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Exchange Mass Spectrometry ◽  
Pparγ Agonist ◽  
A Cell ◽  
And Function

ABSTRACTThe thiazolidinedione (TZD) pioglitazone (Pio) is an FDA-approved drug for type 2 diabetes mellitus that binds and activates the nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ). Although TZDs have potent antidiabetic effects, they also display harmful side effects that have necessitated a better understanding of their mechanisms of action. In particular, little is known about the effect of in vivo TZD metabolites on the structure and function of PPARγ. Here, we present a structure-function comparison of Pio and a major in vivo metabolite, 1-hydroxypioglitazone (PioOH). PioOH displayed a lower binding affinity and reduced potency in coregulator recruitment assays compared to Pio. To determine the structural basis of these findings, we solved an X-ray crystal structure of PioOH bound to PPARγ ligand-binding domain (LBD) and compared it to a published Pio-bound crystal structure. PioOH exhibited an altered hydrogen bonding network that could underlie its reduced affinity and potency compared to Pio. Solution-state structural analysis using NMR spectroscopy and hydrogen/deuterium exchange mass spectrometry (HDX-MS) analysis revealed that PioOH stabilizes the PPARγ activation function-2 (AF-2) coactivator binding surface better than Pio. In support of AF-2 stabilization, PioOH displayed stabilized coactivator binding in biochemical assays and better transcriptional efficacy (maximal transactivation response) in a cell-based assay that reports on the activity of the PPARγ LBD. These results, which indicate that Pio hydroxylation affects both its potency and efficacy as a PPARγ agonist, contribute to our understanding of PPARγ-binding drug metabolite interactions and may assist in future PPARγ drug design efforts.

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