Activation of LXR increases acyl-CoA synthetase activity through direct regulation of ACSL3 in human placental trophoblast cells

Weedon-Fekjær, M.S.; Dalen, Knut Tomas; Solaas, Karianne; Staff, Anne Cathrine; Duttaroy, Asim K.; Nebb, Hilde I.

doi:10.1194/jlr.m004978

Cited by 46 publications

(41 citation statements)

References 61 publications

(71 reference statements)

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“…Activation of LXRs by endogenous ligands of oxidized cholesterol derivatives and pharmaceutical agonists leads to induction of genes involved in reverse cholesterol transport and mobilization of cholesterol, such as the ATP binding cassette (ABC) transporter genes ABCA1, ABCG1, ABCG5, and ABCG8, and genes involved in bile acid synthesis, such as CPY7A ( 25,26 ). Interestingly, a recent report has shown that treating placental trophoblast cells with LXR synthetic ligands stimulated ACSL3 gene transcription, and this effect was mapped to a LXRE motif located 163 bp upstream of the transcription start site ( 27 ), which is downstream of PPRE sites. This study further showed that in cultured human placental BeWo cells, in addition to ACSL3, ACSL5 and ACSL6 were induced by an LXR agonist, implying that these three ACSL isozymes could all be the downstream targets of LXR signaling pathways ( 27 ).…”

Section: Animal Dietsmentioning

confidence: 99%

“…Interestingly, a recent report has shown that treating placental trophoblast cells with LXR synthetic ligands stimulated ACSL3 gene transcription, and this effect was mapped to a LXRE motif located 163 bp upstream of the transcription start site ( 27 ), which is downstream of PPRE sites. This study further showed that in cultured human placental BeWo cells, in addition to ACSL3, ACSL5 and ACSL6 were induced by an LXR agonist, implying that these three ACSL isozymes could all be the downstream targets of LXR signaling pathways ( 27 ).…”

Section: Animal Dietsmentioning

confidence: 99%

“…isolated a 196 bp fragment of the hamster ACSL3 proximal promoter region that contains a sequence motif that is highly homologous to the corresponding human and mouse ACSL3-LXRE sequences ( 27 ) ( Fig. 5A ).…”

Section: Reduction Of Hepatic Acyl-coa Synthetase Activity By Fructosmentioning

confidence: 99%

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High-fructose diet downregulates long-chain acyl-CoA synthetase 3 expression in liver of hamsters via impairing LXR/RXR signaling pathway

Dong

Kan

Singh

et al. 2013

Journal of Lipid Research

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organism under different nutritional environments. This adaptation requires major changes in the hepatic metabolic gene program. One gene family, long-chain acyl-CoA synthetase (ACSL), encodes enzymes that play key roles in lipid metabolism in liver, as well as other metabolic tissues ( 1-5 ). ACSL catalyzes the formation of fatty acyl-CoA from ATP, CoA, and long-chain fatty acids (FAs). This reaction is the fi rst step in FA metabolism following transport of nonesterifi ed FA into mammalian cells. This activation process is essential for cellular utilization of FA via different metabolic pathways, including the cellular ␤ -oxidation system responsible for FA oxidation (catabolism) and the anabolic pathways for the synthesis of phospholipids, cholesterol esters, and triglycerides (TG). To date, fi ve isoforms of ACSL (ACSL1, ACSL3, ACSL4, ACSL5, and ACSL6) have been characterized in humans, mice, and rats ( 3 ). These isoforms differ considerably in their characteristics, including substrate specifi city, enzyme kinetics, and tissue and subcellular distribution. These individual characteristics contribute to their different cellular functions and metabolic outcomes (6)(7)(8)(9)(10)(11)(12)(13)(14). Because each isoform of the ACSL family has a distinct function in directing acyl-CoA to one or more specifi c downstream pathways, the level of expression/activity of individual ACSL isozymes could directly infl uence FA metabolic fates in liver tissue.Nutritional status and hormone levels differently affect the gene expression of ACSL family members in liver tissue ( 15-17 ). In mice fed a normal chow diet, fasting increased the mRNA abundance of ACSL4 and ACSL1 in the liver, and fasting decreased ACSL3 and ACSL5 mRNA levels. In liver of Wister rat, fasting had little effect on ACSL5 mRNA expression, but refeeding markedly increased Abstract Long-chain acyl-CoA synthetases (ACSL) play key roles in fatty acid metabolism in liver and other metabolic tissues in an isozyme-specifi c manner. In this study, we examined the effects of a fructose-enriched diet on expressions of ACSL isoforms in the liver of hamsters. We showed that the fructose diet markedly reduced the mRNA and protein expressions of ACSL3 in hamster liver without signifi cant effects on other ACSLs. The decrease in ACSL3 abundance was accompanied by a reduction in ACSL-catalyzed synthesis of arachidonyl-CoA and oleoyl-CoA in liver homogenates of hamsters fed the fructose diet as opposed to normal diet. We further showed that fructose diet specifically reduced expressions of three key components of the LXR signaling pathway, namely, liver X receptor (LXR) ␣ , LXR ␤ , and retinoid X receptor (RXR) ␤ . Exogenous expression and activation of LXR ␣ / ␤ increased hamster ACSL3 promoter activities in a LXR-responsive element (LXRE)-dependent fashion. Finally, we showed that treating hamsters with LXR agonist GW3965 increased hepatic ACSL3 expression without affecting other ACSL isoforms. Furthermore, the ligand-induced increases of ACSL3 expression were accompan...

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Section: Animal Dietsmentioning

confidence: 99%

Section: Animal Dietsmentioning

confidence: 99%

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High-fructose diet downregulates long-chain acyl-CoA synthetase 3 expression in liver of hamsters via impairing LXR/RXR signaling pathway

Dong

Kan

Singh

et al. 2013

Journal of Lipid Research

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“…Key regulators of lipid metabolism modify the expression of ACSL3: The LXR nuclear receptors increased ACSL3 levels in placental trophoblasts (which corresponded to fatty acid uptake [ 63] ), and PPAR ␦ regulated the expression of ACSL3 in hepatoma HepG2 cells ( 64 ). RNAi of ACSL3 in primary hepatocytes decreased the activity of PPAR ␥ and other lipogenic transcription factors ( 65 ).…”

Section: Lipid Droplet Biogenesismentioning

confidence: 99%

The N-terminal region of acyl-CoA synthetase 3 is essential for both the localization on lipid droplets and the function in fatty acid uptake

Poppelreuther

Rudolph

et al. 2012

Journal of Lipid Research

113

110

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This article is available online at http://www.jlr.org developed very early during evolution. Cytosolic lipid droplets (LDs) are the main reservoir of lipids and are common to many if not all eukaryotic cells ( 1 ). LDs have gained much recent interest because of their regulatory role in lipid homeostasis and their implication in metabolic diseases such as obesity and type 2 diabetes ( 2-4 ). They have a unique structure composed of a hydrophobic core surrounded by a phospholipid monolayer containing a specifi c protein composition. Perilipin family proteins and lipid metabolizing enzymes are the most abundant proteins ( 5, 6 ), and proteomic studies have identifi ed many additional constituents ( 7 ). Little is known how proteins are specifi cally targeted to lipid droplets ( 8, 9 ). The biogenesis of LDs likely involves the endoplasmic reticulum, but the mechanism has not been solved and is debated intensely ( 2,3,10 ).Triglycerides are the main species of neutral lipids stored within the LDs of most cell types. The predominant biosynthetic pathway requires three activated fatty acids for each triglyceride molecule. The fatty acids are taken up from the extracellular medium or are derived from endogenous metabolism by fatty acid synthase. In fact, addition of fatty acids is a very effi cient way to induce the formation of LDs ( 4 ). However, fatty acids are chemically quite inert and need to be activated by esterifi cation with CoA ( 11 ). This activation is catalyzed by the family of acylCoA synthetases ( 12 ); physiologically highly relevant are the long chain (ACSL1, -3, -4, -5, -6) and very long chain (ACSVL1, -2, -3, -4, -5, and -6) fatty acyl-CoA synthetase subfamilies ( 13 ). Apart from their obvious enzymatic role, additional functions have been suggested for ACS(V)L family proteins: metabolic channeling of fatty acids toward specifi c metabolic fates [e.g., phospholipid synthesis vs.Abstract Cytosolic lipid droplets (LDs) are storage organelles for neutral lipids derived from endogenous metabolism. Acyl-CoA synthetase family proteins are essential enzymes in this biosynthetic pathway, contributing activated fatty acids. Fluorescence microscopy showed that ACSL3 is localized to the endoplasmic reticulum (ER) and LDs, with the distribution dependent on the cell type and the supply of fatty acids. The N-terminus of ACSL3 was necessary and sufficient for targeting reporter proteins correctly, as demonstrated by subcellular fractionation and confocal microscopy. The N-terminal region of ACSL3 was also found to be functionally required for the enzyme activity. Selective permeabilization and in silico analysis suggest that ACSL3 assumes a hairpin membrane topology, with the N-terminal hydrophobic amino acids forming an amphipathic helix restricted to the cytosolic leafl et of the ER membrane. ACSL3 was effectively translocated from the ER to nascent LDs when neutral lipid synthesis was stimulated by the external addition of fatty acids. Cellular fatty acid uptake was increased by overexpression and reduced b...

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“…A positive correlation between placental LXR mRNA expression and placental free fatty acids was found in preeclampsia (Weedon-Fekjaer et al, 2010b).…”

Section: Lxrs In Placental Pathologiesmentioning

confidence: 88%

Role of Nuclear Receptors Peroxisome Proliferator-Activated Receptors (PPARs) and Liver X Receptors (LXRs) in the Human Placental Pathophysiology

Marceau¹,

Blanchon²,

Lobaccaro³

et al. 2012

Recent Advances in Research on the Human Placenta

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Activation of LXR increases acyl-CoA synthetase activity through direct regulation of ACSL3 in human placental trophoblast cells

Cited by 46 publications

References 61 publications

High-fructose diet downregulates long-chain acyl-CoA synthetase 3 expression in liver of hamsters via impairing LXR/RXR signaling pathway

High-fructose diet downregulates long-chain acyl-CoA synthetase 3 expression in liver of hamsters via impairing LXR/RXR signaling pathway

The N-terminal region of acyl-CoA synthetase 3 is essential for both the localization on lipid droplets and the function in fatty acid uptake

Role of Nuclear Receptors Peroxisome Proliferator-Activated Receptors (PPARs) and Liver X Receptors (LXRs) in the Human Placental Pathophysiology

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