Identification of the promoter elements involved in the stimulation of ASCT2 expression by glutamine availability in HepG2 cells and the probable involvement of FXR/RXR dimers

Bungard, Claire I.; McGivan, J D

doi:10.1016/j.abb.2005.08.016

Cited by 23 publications

(14 citation statements)

References 12 publications

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“…Regulation of ASCT2 gene expression by Gln was previously reported in hepatic epithelial cells (7). The stimulation of expression in response to Gln was shown to involve, in part, binding of FXR/RXR to the ASCT2 promoter (8).…”

Section: Discussionmentioning

confidence: 63%

Luminal leptin inhibits l-glutamine transport in rat small intestine: involvement of ASCT2 and B⁰AT1

Ducroc

Sakar

Fanjul

et al. 2010

American Journal of Physiology-Gastrointestinal and Liver Physi

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is the primary metabolic fuel for enterocytes. Glutamine from the diet is transported into the absorptive cells by two sodium-dependent neutral amino acid transporters present at the apical membrane: ASCT2/SLC1A5 and B 0 AT1/ SLC6A19. We have demonstrated that leptin is secreted into the stomach lumen after a meal and modulates the transport of sugars after binding to its receptors located at the brush border of the enterocytes. The present study was designed to address the effect of luminal leptin on Na ϩ -dependent glutamine (Gln) transport in rat intestine and identify the transporters involved. We found that 0.2 nM leptin inhibited uptake of Gln and phenylalanine (Phe) (substrate of B 0 AT1) using everted intestinal rings. In Ussing chambers, 10 mM Gln absorption followed as Na ϩ -induced short-circuit current was inhibited by leptin in a dose-dependent manner (maximum inhibition at 10 nM; IC50 ϭ ϳ0.1 nM). Phe absorption was also decreased by leptin. Western blot analysis after 3-min incubation of the intestinal loops with 10 mM Gln, showed marked increase of ASCT2 and B 0 AT1 protein in the brush-border membrane that was reduced by rapid preincubation of the intestinal lumen with 1 nM leptin. Similarly, the increase in ASCT2 and B 0 AT1 gene expression induced by 60-min incubation of the intestine with 10 mM Gln was strongly reduced after a short preincubation period with leptin. Altogether these data demonstrate that, in rat, leptin controls the active Gln entry through reduction of both B 0 AT1 and ASCT2 proteins traffic to the apical plasma membrane and modulation of their gene expression.Ussing chamber; intestinal rings; leptin receptor; phenylalanine; qPCR GLUTAMINE (Gln) is the most abundant amino acid in the plasma. It is absorbed by the intestine, making this organ a key player in the whole body Gln homeostasis. As Gln is a precursor of the nucleosides and glucose synthesis and is involved in the acid-base balance in the kidney, it is crucial for the interorgan nitrogen flux. Gln is also the most important energy source for the enterocytes, lymphocytes, and fibroblasts and is necessary for the growth and viability of cells maintained in culture (5). Gln from the diet is transported into the enterocyte by two sodium-dependent neutral amino acid transporters present in the apical membrane: ASCT2 (System ASC) and B 0 AT1 (System B) (6). ASCT2/SLC1A5 shows high affinity for alanine (Ala), serine, cysteine, threonine, and Gln (K 0.5 ϭ ϳ20 M), whereas B 0 AT1/ SLC6A19 is a low-affinity transporter (K 0.5 ranging from 1.4 to 4 mM) with preference for large neutral amino acids, including those with bulky lateral chain as phenylalanine (Phe), a specific substrate for this transporter (6). In the cell, most of the Gln is metabolized to cover its energetic requirements, and the rest is transported to the blood by the basolateral sodium-independent exchanger LAT-2/4F2hc, SLC7A8/SLC3A2 (system L) (6).Leptin was initially described as an adipostatic signal controlling food intake and energy expenditure (32). Toda...

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Section: Discussionmentioning

confidence: 63%

Luminal leptin inhibits l-glutamine transport in rat small intestine: involvement of ASCT2 and B⁰AT1

Ducroc

Sakar

Fanjul

et al. 2010

American Journal of Physiology-Gastrointestinal and Liver Physi

View full text Add to dashboard Cite

show abstract

“…High glucose concentrations (25 mM) upregulate and insulin represses FXR expression in rat primary hepatocytes (74). Glutamine, an amino acid whose facilitated uptake through the transporter ASCT2 is essential for the rapid growth of cancer cells, induces FXR expression in HepG2 hepatoma cells (31,198). Finally, fasting, which is known to promote overexpression of the transcriptional regulator PGC1␣ (PPAR coactivator 1␣), upregulates FXR␣3/4 expression in the liver.…”

Section: B Tissue Distribution Patterns Of Fxrmentioning

confidence: 99%

Role of Bile Acids and Bile Acid Receptors in Metabolic Regulation

Lefèbvre¹,

Cariou²,

Lien³

et al. 2009

Physiological Reviews

1,353

1,273

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The incidence of the metabolic syndrome has taken epidemic proportions in the past decades, contributing to an increased risk of cardiovascular disease and diabetes. The metabolic syndrome can be defined as a cluster of cardiovascular disease risk factors including visceral obesity, insulin resistance, dyslipidemia, increased blood pressure, and hypercoagulability. The farnesoid X receptor (FXR) belongs to the superfamily of ligand-activated nuclear receptor transcription factors. FXR is activated by bile acids, and FXR-deficient (FXR(-/-)) mice display elevated serum levels of triglycerides and high-density lipoprotein cholesterol, demonstrating a critical role of FXR in lipid metabolism. In an opposite manner, activation of FXR by bile acids (BAs) or nonsteroidal synthetic FXR agonists lowers plasma triglycerides by a mechanism that may involve the repression of hepatic SREBP-1c expression and/or the modulation of glucose-induced lipogenic genes. A cross-talk between BA and glucose metabolism was recently identified, implicating both FXR-dependent and FXR-independent pathways. The first indication for a potential role of FXR in diabetes came from the observation that hepatic FXR expression is reduced in animal models of diabetes. While FXR(-/-) mice display both impaired glucose tolerance and decreased insulin sensitivity, activation of FXR improves hyperglycemia and dyslipidemia in vivo in diabetic mice. Finally, a recent report also indicates that BA may regulate energy expenditure in a FXR-independent manner in mice, via activation of the G protein-coupled receptor TGR5. Taken together, these findings suggest that modulation of FXR activity and BA metabolism may open new attractive pharmacological approaches for the treatment of the metabolic syndrome and type 2 diabetes.

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“…In the same report, Bungard and McGivan117 noted that Gln availability upregulates ASCT2, showing Gln‐dependent ASCT2 promoter activity. Later, they demonstrated that the stimulatory effect of Gln on ASCT2 mRNA expression involves binding of FXR/RXR to the ASCT2 promoter because the activity of the FXR promoter was also increased in response to Gln in the same cells 77. Furthermore, Fuchs et al118 reported that antisense RNA targeting ASCT2 elicited apoptosis in human hematoma SK‐Hep cells.…”

Section: Amino Acid Transportersmentioning

confidence: 99%

Solute Carrier Transporters as Targets for Drug Delivery and Pharmacological Intervention for Chemotherapy

Nakanishi

Tamai

2011

Journal of Pharmaceutical Sciences

116

103

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Identification of the promoter elements involved in the stimulation of ASCT2 expression by glutamine availability in HepG2 cells and the probable involvement of FXR/RXR dimers

Cited by 23 publications

References 12 publications

Luminal leptin inhibits l-glutamine transport in rat small intestine: involvement of ASCT2 and B⁰AT1

Luminal leptin inhibits l-glutamine transport in rat small intestine: involvement of ASCT2 and B⁰AT1

Role of Bile Acids and Bile Acid Receptors in Metabolic Regulation

Solute Carrier Transporters as Targets for Drug Delivery and Pharmacological Intervention for Chemotherapy

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Identification of the promoter elements involved in the stimulation of ASCT2 expression by glutamine availability in HepG2 cells and the probable involvement of FXR/RXR dimers

Cited by 23 publications

References 12 publications

Luminal leptin inhibits l-glutamine transport in rat small intestine: involvement of ASCT2 and B0AT1

Luminal leptin inhibits l-glutamine transport in rat small intestine: involvement of ASCT2 and B0AT1

Role of Bile Acids and Bile Acid Receptors in Metabolic Regulation

Solute Carrier Transporters as Targets for Drug Delivery and Pharmacological Intervention for Chemotherapy

Contact Info

Product

Resources

About

Luminal leptin inhibits l-glutamine transport in rat small intestine: involvement of ASCT2 and B⁰AT1

Luminal leptin inhibits l-glutamine transport in rat small intestine: involvement of ASCT2 and B⁰AT1