Endotoxin-induced inflammation down-regulates l-type amino acid transporter 1 (LAT1) expression at the blood-brain barrier of male rats and mice

Gábor Wittmann, Petra Mohácsik, Mumtaz Yaseen Balkhi, B. Gereben, Ronald M. Lechan

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

Background: We recently reported that bacterial lipopolysaccharide (LPS)-induced inflammation decreases the expression of the primary thyroid hormone transporters at the blood-brain barrier, organic anion-transporting polypeptide 1c1 (OATP1c1) and monocarboxylate transporter 8 (MCT8). l-type amino acid transporters 1 and 2 (LAT1 & LAT2) are regarded as secondary thyroid hormone transporters, and are expressed in cells of the blood-brain or blood-cerebrospinal fluid barrier and by neurons. The purpose of this study was to examine the effect of LPS-induced inflammation on the expression of LAT1 and LAT2, as these may compensate for the downregulation of OATP1c1 and MCT8. Methods: LPS (2.5mg/kg body weight) was injected intraperitoneally to adult, male, Sprague-Dawley rats and C57Bl/6 mice, which were euthanized 2, 4, 9, 24 or 48h later. LAT1 and LAT2 mRNA expression were studied on forebrain sections using semiquantitative radioactive in situ hybridization. LAT1 protein levels in brain vessels were studied using LAT1 immunofluorescence. Statistical comparisons were made by the non-parametric Kruskal-Wallis and Dunn's tests. Results: In both species, LAT1 mRNA decreased in brain blood vessels as soon as 2h after LPS injection and was virtually undetectable at 4h and 9h. During recovery from endotoxemia, 48h after LPS injection, LAT1 mRNA in brain vessels increased above control levels. A modest but significant decrease in LAT1 protein levels was detected in the brain vessels of mice at 24h following LPS injection. LPS did not affect LAT1 and LAT2 mRNA expression in neurons and choroid plexus epithelial cells. Conclusions: The results demonstrate that LPS-induced inflammation rapidly decreases LAT1 mRNA expression at the blood-brain barrier in a very similar manner to primary thyroid hormone transporters, while changes in LAT1 protein level follow a slower kinetics. The data raise the possibility that inflammation may similarly down-regulate other blood-brain barrier transport systems at the transcriptional level. Future studies are required to examine this possibility and the potential pathophysiological consequences of inflammation-induced changes in blood-brain barrier transport functions.

Original languageEnglish
Article number21
JournalFluids and Barriers of the CNS
Volume12
Issue number1
DOIs
Publication statusPublished - Sep 4 2015

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Amino Acid Transport Systems
Blood-Brain Barrier
Endotoxins
Down-Regulation
Inflammation
Lipopolysaccharides
Messenger RNA
Thyroid Hormones
Brain
Injections
Anions
Neurons
Peptides
Proteins
Choroid Plexus
Endotoxemia
Prosencephalon
In Situ Hybridization
Fluorescent Antibody Technique
Blood Vessels

Keywords

  • Amino acid transport
  • Blood-brain barrier
  • Inflammation
  • LAT1
  • LPS
  • Thyroid hormone

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Neurology
  • Developmental Neuroscience

Cite this

Endotoxin-induced inflammation down-regulates l-type amino acid transporter 1 (LAT1) expression at the blood-brain barrier of male rats and mice. / Wittmann, Gábor; Mohácsik, Petra; Balkhi, Mumtaz Yaseen; Gereben, B.; Lechan, Ronald M.

In: Fluids and Barriers of the CNS, Vol. 12, No. 1, 21, 04.09.2015.

Research output: Contribution to journalArticle

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AU - Gereben, B.

AU - Lechan, Ronald M.

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N2 - Background: We recently reported that bacterial lipopolysaccharide (LPS)-induced inflammation decreases the expression of the primary thyroid hormone transporters at the blood-brain barrier, organic anion-transporting polypeptide 1c1 (OATP1c1) and monocarboxylate transporter 8 (MCT8). l-type amino acid transporters 1 and 2 (LAT1 & LAT2) are regarded as secondary thyroid hormone transporters, and are expressed in cells of the blood-brain or blood-cerebrospinal fluid barrier and by neurons. The purpose of this study was to examine the effect of LPS-induced inflammation on the expression of LAT1 and LAT2, as these may compensate for the downregulation of OATP1c1 and MCT8. Methods: LPS (2.5mg/kg body weight) was injected intraperitoneally to adult, male, Sprague-Dawley rats and C57Bl/6 mice, which were euthanized 2, 4, 9, 24 or 48h later. LAT1 and LAT2 mRNA expression were studied on forebrain sections using semiquantitative radioactive in situ hybridization. LAT1 protein levels in brain vessels were studied using LAT1 immunofluorescence. Statistical comparisons were made by the non-parametric Kruskal-Wallis and Dunn's tests. Results: In both species, LAT1 mRNA decreased in brain blood vessels as soon as 2h after LPS injection and was virtually undetectable at 4h and 9h. During recovery from endotoxemia, 48h after LPS injection, LAT1 mRNA in brain vessels increased above control levels. A modest but significant decrease in LAT1 protein levels was detected in the brain vessels of mice at 24h following LPS injection. LPS did not affect LAT1 and LAT2 mRNA expression in neurons and choroid plexus epithelial cells. Conclusions: The results demonstrate that LPS-induced inflammation rapidly decreases LAT1 mRNA expression at the blood-brain barrier in a very similar manner to primary thyroid hormone transporters, while changes in LAT1 protein level follow a slower kinetics. The data raise the possibility that inflammation may similarly down-regulate other blood-brain barrier transport systems at the transcriptional level. Future studies are required to examine this possibility and the potential pathophysiological consequences of inflammation-induced changes in blood-brain barrier transport functions.

AB - Background: We recently reported that bacterial lipopolysaccharide (LPS)-induced inflammation decreases the expression of the primary thyroid hormone transporters at the blood-brain barrier, organic anion-transporting polypeptide 1c1 (OATP1c1) and monocarboxylate transporter 8 (MCT8). l-type amino acid transporters 1 and 2 (LAT1 & LAT2) are regarded as secondary thyroid hormone transporters, and are expressed in cells of the blood-brain or blood-cerebrospinal fluid barrier and by neurons. The purpose of this study was to examine the effect of LPS-induced inflammation on the expression of LAT1 and LAT2, as these may compensate for the downregulation of OATP1c1 and MCT8. Methods: LPS (2.5mg/kg body weight) was injected intraperitoneally to adult, male, Sprague-Dawley rats and C57Bl/6 mice, which were euthanized 2, 4, 9, 24 or 48h later. LAT1 and LAT2 mRNA expression were studied on forebrain sections using semiquantitative radioactive in situ hybridization. LAT1 protein levels in brain vessels were studied using LAT1 immunofluorescence. Statistical comparisons were made by the non-parametric Kruskal-Wallis and Dunn's tests. Results: In both species, LAT1 mRNA decreased in brain blood vessels as soon as 2h after LPS injection and was virtually undetectable at 4h and 9h. During recovery from endotoxemia, 48h after LPS injection, LAT1 mRNA in brain vessels increased above control levels. A modest but significant decrease in LAT1 protein levels was detected in the brain vessels of mice at 24h following LPS injection. LPS did not affect LAT1 and LAT2 mRNA expression in neurons and choroid plexus epithelial cells. Conclusions: The results demonstrate that LPS-induced inflammation rapidly decreases LAT1 mRNA expression at the blood-brain barrier in a very similar manner to primary thyroid hormone transporters, while changes in LAT1 protein level follow a slower kinetics. The data raise the possibility that inflammation may similarly down-regulate other blood-brain barrier transport systems at the transcriptional level. Future studies are required to examine this possibility and the potential pathophysiological consequences of inflammation-induced changes in blood-brain barrier transport functions.

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KW - LPS

KW - Thyroid hormone

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