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Cited by 43Barrier Structure and Function StudiesAmino Acid Enzymes and MetabolismDrug Transport and Resistance Mechanisms

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

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Wittmann, Gábor, Mohácsik, Petra, Balkhi, Mumtaz Yaseen, Gereben, Balázs, Lechan, Ronald M.·2015·Fluids and Barriers of the CNS
DOI 10.1186/s12987-015-0016-8PMC PMC4559167
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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 (2.5 mg/kg body weight) was injected intraperitoneally to adult, male, Sprague-Dawley rats and C57Bl/6 mice, which were euthanized 2, 4, 9, 24 or 48 h 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 2 h after LPS injection and was virtually undetectable at 4 h and 9 h. During recovery from endotoxemia, 48 h 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 24 h 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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  • The low level of T3 and T4 transport in MCT8-deficient cells may be attributed to expression of additional transporters LAT1, LAT2, and OATP1C1.

    “which may be attributed to the expression of the additional transporters LAT1, LAT2, and OATP1C1 (Heuer and Visser, 2013; Wittmann et al., 2015).”

    From Modeling Psychomotor Retardation using iPSCs from MCT8-Deficient Patients Indicates a Prominent Role for the Blood-Brain Barrier (2017) · cites this paper as Wittmann et al., 2015

    The Background (page unavailable) identifies OATP1c1 as a thyroid-hormone transporter and says LAT1 and LAT2 can also transport thyroid hormone. It does not establish that these transporters are expressed in the MCT8-deficient cells at issue or account for their low residual T3 and T4 transport. (LLM, conf=0.85)

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Authors
Wittmann, G., Mohácsik, P., Balkhi, M. Y., Gereben, B., & Lechan, R. M.
Affiliations
  • Tufts Medical Center (US)
  • Semmelweis University (HU)
  • HUN-REN Institute of Experimental Medicine (HU)
  • Tufts University (US)
Corresponding author
  • Wittmann, Gábor
  • Lechan, Ronald M.
ORCID
Venue
Fluids and Barriers of the CNS
Publisher
Springer Science and Business Media LLC
Published
2015-09-04
Volume
12
Issue
1
Pages
21-21
ISSN
2045-8118 (ISSN-L)
DOI
10.1186/s12987-015-0016-8
PMC
PMC4559167
OpenAlex
W1762915743
Cited by
43
References
50
Citations by year
2026: 4 · 2025: 4 · 2024: 3 · 2023: 5 · 2022: 5 · 2021: 2 · 2020: 3 · 2019: 4 · 2018: 4 · 2017: 6 · 2016: 3
FWCI
2.32
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Fluids and Barriers of the CNS (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • Dr. Gerald J. and Dorothy R. Friedman New York Foundation for Medical Research
  • Országos Tudományos Kutatási Alapprogramok (OTKA109415)
Topics
  • Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
  • Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
Keywords
endotoxin, lipopolysaccharide, inflammation, blood-brain barrier, LAT1, LAT2, thyroid hormone transporters, OATP1C1, MCT8, endotoxemia, gene downregulation, brain vessels, choroid plexus epithelial cells, rats, mice
MeSH terms
Animals, Blood-Brain Barrier, Encephalitis, Lipopolysaccharides, Male, Mice, Inbred C57BL, Neurons, RNA, Messenger, Prosencephalon, Rats, Sprague-Dawley, Amino Acid Transport System y+, Mice, Rats

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