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The role of SLC transporters for brain health and disease

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Abstract

The brain exchanges nutrients and small molecules with blood via the blood–brain barrier (BBB). Approximately 20% energy intake for the body is consumed by the brain. Glucose is known for its critical roles for energy production and provides substrates for biogenesis in neurons. The brain takes up glucose via glucose transporters GLUT1 and 3, which are expressed in several neural cell types. The brain is also equipped with various transport systems for acquiring amino acids, lactate, ketone bodies, lipids, and cofactors for neuronal functions. Unraveling the mechanisms by which the brain takes up and metabolizes these nutrients will be key in understanding the nutritional requirements in the brain. This could also offer opportunities for therapeutic interventions in several neurological disorders. For instance, emerging evidence suggests a critical role of lactate as an alternative energy source for neurons. Neuronal cells express monocarboxylic transporters to acquire lactate. As such, treatment of GLUT1-deficient patients with ketogenic diets to provide the brain with alternative sources of energy has been shown to improve the health of the patients. Many transporters are present in the brain, but only a small number has been characterized. In this review, we will discuss about the roles of solute carrier (SLC) transporters at the blood brain barrier (BBB) and neural cells, in transport of nutrients and metabolites in the brain.

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Abbreviations

ABC transporter:

ATP-binding cassette transporter

AD:

Alzheimer’s disease

ADHD:

Attention-deficit/hyperactivity disorder

AHDS:

Allan–Herndon–Dudley syndrome

Akt:

Serine/threonine protein kinase

APP:

Amyloid precursor protein

APP/PS1:

APPswe/PS1dE9

Aß peptide:

ß-amyloid peptide

ASD:

Autism spectrum disorders

ASYMAD:

Asymptomatic AD

ATP:

Adenosine triphosphate

Aβ:

Amyloid β-peptide

BBB:

Blood–brain barrier

CD31:

Cluster of differentiation 31

CD36:

Cluster of differentiation 36

CD4:

Cluster of differentiation 4

CNS:

Central nervous system

CNV:

Copy number variation

CREB:

CAMP-response element

D2:

Type 2 deiodinase

DHA:

Docosahexaenoic acid

EAAT:

Excitatory amino acid transporters

ECs:

Endothelial cells

ED:

Epileptiform discharges

EEG:

Electroencephalography

EGF:

Epidermal growth factor

EMT:

Extra-neuronal monoamine transporter

ENU:

N-Ethyl-N-nitrosourea

FAD:

Flavin adenine dinucleotide

FAs:

Fatty acids

FAT:

Fatty acid translocase

FATP:

Fatty acid transport proteins

FMN:

Flavin mononucleotide

GAA:

Guanidinoacetate

GBM:

Glioblastoma

GLUT:

Glucose transporter

GLUT1-DS:

GLUT1 deficiency

GLUT1-DS:

GLUT1 deficiency syndrome

GSCs:

GBM cancer stem cells

GT1AS:

Antisense-GLUT1 cDNA

hCMEC/D3:

Human brain endothelial cells

His:

Histidine

HMGA1:

The high mobility Group A1

HRE:

Hypoxia-responsive element

HTLV:

Human T-lymphotropic virus

IGF-1:

Insulin-like growth factor 1

Ile:

Isoleucine

KO:

Knock-out

LAT:

L amino acid transporter

LDHB:

Lactate dehydrogenase B

Leu:

Leucine

LRP1:

Low-density lipoprotein receptor-related protein 1

MCTs:

Monocarboxylate transporters

Met:

Methionine

MFS:

Major facilitator superfamily

Mfsd2a:

Major facilitator superfamily domain-containing protein 2a

mTOR:

Mammalian target of rapamycin

N- and C-termini:

Amino and carboxyl termini

NF-kB:

Nuclear factor kappa-light-chain-enhancer of activated B cells

NFTs:

Neurofibrillary tangles

Oatp1c1:

Organic anion transporter polypeptide 1c1

OCTN:

Organic cation novel transporter

PEST domains:

Domains enriched of Pro, Glu, Ser, Thr

Phe:

Phenylalanine

PI3K:

Phosphatidylinositol 3-kinase

PKC:

Protein kinase C

RA:

Rheumatoid arthritis

RFVT1:

Riboflavin transporter 1

RFVT2:

Riboflavin transporter 2

RFVT3:

Riboflavin transporter 3

ROS:

Reactive oxygen species

SLC16:

Solute carrier 16

SLC52:

Solute carrier family 52

SVCT:

Sodium-dependent vitamin C transporter

T3 :

3,5,3′-Triiodothyronine

T4 :

Thyroxine

Thr:

Threonine

TLS:

Translation start site

Trp:

Tryptophan

TRs:

Thyroid hormone receptors

TSC1/2:

Tuberous sclerosis proteins 1/2

TXNIP:

Identification of thioredoxin-interacting protein

Tyr:

Tyrosine

UDP-glucose:

Uracil-diphosphate glucose

Val:

Valine

VE-Cadherin:

Vascular endothelial (VE)-cadherin

VEGFR2:

Vascular endothelial growth factor receptor 2

Wnt:

Wingless-related integration site

References

  1. Mergenthaler P et al (2013) Sugar for the brain: the role of glucose in physiological and pathological brain function. Trends Neurosci 36(10):587–597

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Watts ME, Pocock R, Claudianos C (2018) Brain energy and oxygen metabolism: emerging role in normal function and disease. Front Mol Neurosci 11:216

    PubMed  PubMed Central  Google Scholar 

  3. Sweeney MD, Sagare AP, Zlokovic BV (2018) Blood-brain barrier breakdown in Alzheimer disease and other neurodegenerative disorders. Nat Rev Neurol 14(3):133–150

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Vanlandewijck M et al (2018) A molecular atlas of cell types and zonation in the brain vasculature. Nature 554(7693):475–480

    CAS  PubMed  Google Scholar 

  5. Lauritzen KH et al (2014) Lactate receptor sites link neurotransmission, neurovascular coupling, and brain energy metabolism. Cereb Cortex 24(10):2784–2795

    PubMed  Google Scholar 

  6. Bergersen LH, Gjedde A (2012) Is lactate a volume transmitter of metabolic states of the brain? Front Neuroenergetics 4:5–5

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Veech RL (1991) The metabolism of lactate. NMR Biomed 4:53–58

    CAS  PubMed  Google Scholar 

  8. Dienel GA (2012) Brain lactate metabolism: the discoveries and the controversies. J Cereb Blood Flow Metab 32(7):1107–1138

    CAS  PubMed  Google Scholar 

  9. Cataldo AM, Broadwell RD (1986) Cytochemical identification of cerebral glycogen and glucose-6-phosphatase activity under normal and experimental conditions: I. Neurons and glia. J Electron Microsc Tech 3(4):413–437

    CAS  Google Scholar 

  10. Dienel GA, Cruz NF (2015) Contributions of glycogen to astrocytic energetics during brain activation. Metab Brain Dis 30(1):281–298

    CAS  PubMed  Google Scholar 

  11. Suzuki A et al (2011) Astrocyte-neuron lactate transport is required for long-term memory formation. Cell 144(5):810–823

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Poitelon Y, Kopec AM, Belin S (2020) Myelin fat facts: an overview of lipids and fatty acid metabolism. Cells 9(4):812–812

    CAS  PubMed Central  Google Scholar 

  13. Wakil SJ, Stoops JK, Joshi VC (1983) fatty acid synthesis and its regulation. Annu Rev Biochem 52(1):537–579

    CAS  PubMed  Google Scholar 

  14. Röder PV et al (2016) Pancreatic regulation of glucose homeostasis. Exp Mol Med 48(3):e219–e219

    PubMed  PubMed Central  Google Scholar 

  15. Ritter S (2017) Monitoring and maintenance of brain glucose supply: importance of hindbrain catecholamine neurons in this multifaceted task. In: Harris RBS (ed) BTI—appetite and food intake: central control, in appetite and food intake: central control, 2nd edn. CRC Press, Boca Raton

  16. Meierhans R et al (2010) Brain metabolism is significantly impaired at blood glucose below 6 mM and brain glucose below 1 mM in patients with severe traumatic brain injury. Crit Care (London, England) 14(1):R13–R13

    Google Scholar 

  17. Wright EM, Loo DD, Hirayama BA (2011) Biology of human sodium glucose transporters. Physiol Rev 91(2):733–794

    CAS  PubMed  Google Scholar 

  18. Mueckler M, Thorens B (2013) The SLC2 (GLUT) family of membrane transporters. Mol Aspects Med 34(2–3):121–138

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Holman GD (2020) Structure, function and regulation of mammalian glucose transporters of the SLC2 family. Pflügers Arch Eur J Physiol 472(9):1155–1175

    CAS  Google Scholar 

  20. Gorovits N, Charron MJ (2003) What we know about facilitative glucose transporters: lessons from cultured cells, animal models, and human studies. Biochem Mol Biol Educ 31(3):163–172

    CAS  Google Scholar 

  21. Harvey Lodish AB, Lawrence Z, Paul M, David B, James D (2000) Section 15.3: uniporter-catalyzed transport. In: molecular cell biology, 4th edn. W H Freeman & Co (Sd), New York

  22. Deng D et al (2014) Crystal structure of the human glucose transporter GLUT1. Nature 510(7503):121–125

    CAS  PubMed  Google Scholar 

  23. Sun Y et al (2019) sgRNA-shRNA structure mediated SNP site editing on porcine IGF2 gene by CRISPR/StCas9. Front Genet 10:347

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Devraj K et al (2011) GLUT-1 glucose transporters in the blood-brain barrier: differential phosphorylation. J Neurosci Res 89(12):1913–1925

    CAS  PubMed  Google Scholar 

  25. Duelli R, Kuschinsky W (2001) Brain glucose transporters: relationship to local energy demand. Physiology 16(2):71–76

    CAS  Google Scholar 

  26. Simpson IA et al (2008) The facilitative glucose transporter GLUT3: 20 years of distinction. Am J Physiol Endocrinol Metab 295(2):E242–E253

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Maher F, Simpson IA (1994) The GLUT3 glucose transporter is the predominant isoform in primary cultured neurons: assessment by biosynthetic and photoaffinity labelling. Biochem J 301((Pt 2)):379–384

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Messana T et al (2018) Glucose transporter type 1 deficiency syndrome: developmental delay and early-onset ataxia in a novel mutation of the SLC2A1 gene. J Pediatr Neurosci 13(4):496–499

    PubMed  PubMed Central  Google Scholar 

  29. Asano T et al (1991) The role of N-glycosylation of GLUT1 for glucose transport activity. J Biol Chem 266(36):24632–24636

    CAS  PubMed  Google Scholar 

  30. Thorens B, Mueckler M (2010) Glucose transporters in the 21st Century. Am J Physiol Endocrinol Metab 298(2):E141–E145

    CAS  PubMed  Google Scholar 

  31. Korotcov AV et al (2012) Glucosamine-linked near-infrared fluorescent probes for imaging of solid tumor xenografts. Mol Imag Biol 14(4):443–451

    Google Scholar 

  32. Wang Y-Z et al (2018) Brain transport profiles of Ginsenoside Rb1 by glucose transporter 1: in vitro and in vivo. Front Pharmacol. https://doi.org/10.3389/fphar.2018.00398

    Article  PubMed  PubMed Central  Google Scholar 

  33. Kasahara T et al (2009) Identification of a key residue determining substrate affinity in the human glucose transporter GLUT1. Biochim Biophys Acta (BBA) 1788(5):1051–1055

    CAS  Google Scholar 

  34. Kapoor K et al (2016) Mechanism of inhibition of human glucose transporter GLUT1 is conserved between cytochalasin B and phenylalanine amides. Proc Natl Acad Sci 113(17):4711

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Siska PJ, Rathmell JC (2015) PKCs sweeten cell metabolism by phosphorylation of Glut1. Mol Cell 58(5):711–712

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Nasoohi S, Ismael S, Ishrat T (2018) Thioredoxin-interacting protein (TXNIP) in cerebrovascular and neurodegenerative diseases: regulation and implication. Mol Neurobiol 55(10):7900–7920

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Wang D et al (2006) A mouse model for Glut-1 haploinsufficiency. Hum Mol Genet 15(7):1169–1179

    CAS  PubMed  Google Scholar 

  38. Heilig CW et al (2003) Glucose transporter-1-deficient mice exhibit impaired development and deformities that are similar to diabetic embryopathy. Proc Natl Acad Sci USA 100(26):15613–15618

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Furuse T et al (2019) A new mouse model of GLUT1 deficiency syndrome exhibits abnormal sleep-wake patterns and alterations of glucose kinetics in the brain. Disease Models Mech 12(9):dmm038828

    CAS  Google Scholar 

  40. Zheng P-P et al (2010) Glut1/SLC2A1 is crucial for the development of the blood-brain barrier in vivo. Ann Neurol 68(6):835–844

    CAS  PubMed  Google Scholar 

  41. Tang M et al (2017) Brain microvasculature defects and Glut1 deficiency syndrome averted by early repletion of the glucose transporter-1 protein. Nat Commun 8:14152–14152

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Vaudano AE et al (2017) Brain correlates of spike and wave discharges in GLUT1 deficiency syndrome. Neuroimage Clin 13:446–454

    PubMed  Google Scholar 

  43. Sánchez Fernández I et al (2015) Should epileptiform discharges be treated? Epilepsia 56(10):1492–1504

    PubMed  Google Scholar 

  44. Aldenkamp AP, Arends J (2004) Effects of epileptiform EEG discharges on cognitive function: is the concept of “transient cognitive impairment” still valid? Epilepsy Behav 5(Suppl 1):S25-34

    PubMed  Google Scholar 

  45. Veys K et al (2020) Role of the glut1 glucose transporter in postnatal CNS angiogenesis and blood–brain barrier integrity. Circ Res 127(4):466–482

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Ziegler GC et al (2020) Cellular effects and clinical implications of SLC2A3 copy number variation. J Cell Physiol 235(12):9021–9036

    CAS  PubMed  Google Scholar 

  47. Yano H et al (1991) Tissue distribution and species difference of the brain type glucose transporter (GLUT3). Biochem Biophys Res Commun 174(2):470–477

    CAS  PubMed  Google Scholar 

  48. Leino RL et al (1997) Ultrastructural localization of GLUT 1 and GLUT 3 glucose transporters in rat brain. J Neurosci Res 49(5):617–626

    CAS  PubMed  Google Scholar 

  49. Rumsey S et al (1997) Glucose transporter isoforms GLUT1 and GLUT3 transport dehydroascorbic acid. J Biol Chem 272:18982–18989

    CAS  PubMed  Google Scholar 

  50. Burant CF, Bell GI (1992) Mammalian facilitative glucose transporters: evidence for similar substrate recognition sites in functionally monomeric proteins. Biochemistry 31(42):10414–10420

    CAS  PubMed  Google Scholar 

  51. Heilig C et al (2003) Implications of glucose transporter protein type 1 (GLUT1)-haplodeficiency in embryonic stem cells for their survival in response to hypoxic stress. Am J Pathol 163(5):1873–1885

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Patching SG (2017) Glucose transporters at the blood-brain barrier: function, regulation and gateways for drug delivery. Mol Neurobiol 54(2):1046–1077

    CAS  PubMed  Google Scholar 

  53. Ganguly A et al (2007) Glucose transporter isoform-3 mutations cause early pregnancy loss and fetal growth restriction. Am J Physiol Endocrinol Metab 292(5):E1241–E1255

    CAS  PubMed  Google Scholar 

  54. Schmidt S et al (2008) Neuronal functions, feeding behavior, and energy balance in Slc2a3+/− mice. Am J Physiol Endocrinol Metab 295(5):E1084–E1094

    CAS  PubMed  Google Scholar 

  55. Shin B-C et al (2018) Neural deletion of glucose transporter isoform 3 creates distinct postnatal and adult neurobehavioral phenotypes. J Neurosci 38(44):9579–9599

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Stuart CA et al (2011) Brain glucose transporter (Glut3) haploinsufficiency does not impair mouse brain glucose uptake. Brain Res 1384:15–22

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Arsov T et al (2012) Early onset absence epilepsy: 1 in 10 cases is caused by GLUT1 deficiency. Epilepsia 53(12):e204–e207

    PubMed  Google Scholar 

  58. Rotstein M et al (2010) Glut1 deficiency: inheritance pattern determined by haploinsufficiency. Ann Neurol 68(6):955–958

    PubMed  PubMed Central  Google Scholar 

  59. Wang D et al (2005) Glut-1 deficiency syndrome: clinical, genetic, and therapeutic aspects. Ann Neurol 57(1):111–118

    CAS  PubMed  Google Scholar 

  60. Klepper J et al (2020) Glut1 Deficiency Syndrome (Glut1DS): State of the art in 2020 and recommendations of the international Glut1DS study group. Epilepsia Open 5(3):354–365

    PubMed  PubMed Central  Google Scholar 

  61. Pascual JM et al (2014) Triheptanoin for glucose transporter type I deficiency (G1D): modulation of human ictogenesis, cerebral metabolic rate, and cognitive indices by a food supplement. JAMA Neurol 71(10):1255–1265

    PubMed  PubMed Central  Google Scholar 

  62. Lane CA, Hardy J, Schott JM (2018) Alzheimer’s disease. Eur J Neurol 25(1):59–70

    CAS  PubMed  Google Scholar 

  63. Murphy MP, LeVine H 3rd (2010) Alzheimer’s disease and the amyloid-beta peptide. J Alzheimer’s Dis 19(1):311–323

    Google Scholar 

  64. Lee HJ et al (2018) Diabetes and Alzheimer’s disease: mechanisms and nutritional aspects. Clin Nutr Res 7(4):229–240

    PubMed  PubMed Central  Google Scholar 

  65. Dineley KT, Jahrling JB, Denner L (2014) Insulin resistance in Alzheimer’s disease. Neurobiol Dis 72(Pt A):92–103

    CAS  PubMed  Google Scholar 

  66. Cholerton B et al (2016) Type 2 diabetes, cognition, and dementia in older adults: toward a precision health approach. Diabetes Spectr 29(4):210–219

    PubMed  PubMed Central  Google Scholar 

  67. Winkler EA et al (2015) GLUT1 reductions exacerbate Alzheimer’s disease vasculo-neuronal dysfunction and degeneration. Nat Neurosci 18(4):521–530

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Ramanathan A et al (2015) Impaired vascular-mediated clearance of brain amyloid beta in Alzheimer’s disease: the role, regulation and restoration of LRP1. Front Aging Neurosci 7:136

    PubMed  PubMed Central  Google Scholar 

  69. Zlokovic BV et al (2010) Low-density lipoprotein receptor-related protein-1: a serial clearance homeostatic mechanism controlling Alzheimer’s amyloid β-peptide elimination from the brain. J Neurochem 115(5):1077–1089

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Zhao Z et al (2015) Central role for PICALM in amyloid-β blood-brain barrier transcytosis and clearance. Nat Neurosci 18(7):978–987

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Donahue JE et al (2006) RAGE, LRP-1, and amyloid-beta protein in Alzheimer’s disease. Acta Neuropathol 112(4):405–415

    CAS  PubMed  Google Scholar 

  72. Driscoll I, Troncoso J (2011) Asymptomatic Alzheimer’s disease: a prodrome or a state of resilience? Curr Alzheimer Res 8(4):330–335

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Liu Y et al (2009) Brain glucose transporters, O-GlcNAcylation and phosphorylation of tau in diabetes and Alzheimer’s disease. J Neurochem 111(1):242–249

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Flavahan WA et al (2013) Brain tumor initiating cells adapt to restricted nutrition through preferential glucose uptake. Nat Neurosci 16(10):1373–1382

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Kuang R et al (2017) GLUT3 upregulation promotes metabolic reprogramming associated with antiangiogenic therapy resistance. JCI Insight 2(2):e88815

    PubMed  PubMed Central  Google Scholar 

  76. Kuo M-H et al (2019) Glucose transporter 3 is essential for the survival of breast cancer cells in the brain. Cells 8(12):1568

    CAS  PubMed Central  Google Scholar 

  77. Yu J et al (2012) IGF-1 induces hypoxia-inducible factor 1α-mediated GLUT3 expression through PI3K/Akt/mTOR dependent pathways in PC12 cells. Brain Res 1430:18–24

    CAS  PubMed  Google Scholar 

  78. Zhang Z et al (2018) PI3K/Akt and HIF-1 signaling pathway in hypoxia-ischemia (Review). Mol Med Rep 18(4):3547–3554

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Libby CJ et al (2018) Identification of compounds that decrease glioblastoma growth and glucose uptake in vitro. ACS Chem Biol 13(8):2048–2057

    CAS  PubMed Central  Google Scholar 

  80. Halestrap AP, Meredith D (2004) The SLC16 gene family-from monocarboxylate transporters (MCTs) to aromatic amino acid transporters and beyond. Pflugers Arch 447(5):619–628

    CAS  PubMed  Google Scholar 

  81. Halestrap AP, Price NT (1999) The proton-linked monocarboxylate transporter (MCT) family: structure, function and regulation. Biochem J 343(Pt 2):281–299

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Halestrap AP (2013) The SLC16 gene family—structure, role and regulation in health and disease. Mol Aspects Med 34(2–3):337–349

    CAS  PubMed  Google Scholar 

  83. Murakami Y et al (2005) Functional characterization of human monocarboxylate transporter 6 (SLC16A5). Drug Metab Dispos 33(12):1845–1851

    CAS  PubMed  Google Scholar 

  84. Jones RS et al (2019) Characterization and proteomic-transcriptomic investigation of monocarboxylate transporter 6 knockout mice: evidence of a potential role in glucose and lipid metabolism. Mol Pharmacol 96(3):364–376

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Dai W et al (2020) Genetic variants in PDSS1 and SLC16A6 of the ketone body metabolic pathway predict cutaneous melanoma-specific survival. Mol Carcinog 59(6):640–650

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Karanth S, Schlegel A (2018) The monocarboxylate transporter SLC16A6 regulates adult length in zebrafish and is associated with height in humans. Front Physiol 9:1936

    PubMed  Google Scholar 

  87. Friesema EC et al (2003) Identification of monocarboxylate transporter 8 as a specific thyroid hormone transporter. J Biol Chem 278(41):40128–40135

    CAS  PubMed  Google Scholar 

  88. Friesema EC et al (2008) Effective cellular uptake and efflux of thyroid hormone by human monocarboxylate transporter 10. Mol Endocrinol 22(6):1357–1369

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Suhre K et al (2011) Human metabolic individuality in biomedical and pharmaceutical research. Nature 477(7362):54–60

    CAS  PubMed  Google Scholar 

  90. Jansen L et al (2014) HBsAg loss in patients treated with peginterferon alfa-2a and adefovir is associated with SLC16A9 gene variation and lower plasma carnitine levels. J Hepatol 61(4):730–737

    CAS  PubMed  Google Scholar 

  91. Almeda-Valdes P et al (2019) The SLC16A11 risk haplotype is associated with decreased insulin action, higher transaminases and large-size adipocytes. Eur J Endocrinol 180(2):99–107

    CAS  PubMed  Google Scholar 

  92. Abplanalp J et al (2013) The cataract and glucosuria associated monocarboxylate transporter MCT12 is a new creatine transporter. Hum Mol Genet 22(16):3218–3226

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Jomura R et al (2020) Monocarboxylate transporter 12 as a guanidinoacetate efflux transporter in renal proximal tubular epithelial cells. Biochim Biophys Acta Biomembr 1862(11):183434

    CAS  PubMed  Google Scholar 

  94. Takahashi M et al (2020) Functional characterization of monocarboxylate transporter 12 (SLC16A12/MCT12) as a facilitative creatine transporter. Drug Metab Pharmacokinet 35(3):281–287

    CAS  PubMed  Google Scholar 

  95. Rafiki A et al (2003) Highly differential expression of the monocarboxylate transporters MCT2 and MCT4 in the developing rat brain. Neuroscience 122(3):677–688

    CAS  PubMed  Google Scholar 

  96. Halestrap AP, Wilson MC (2012) The monocarboxylate transporter family–role and regulation. IUBMB Life 64(2):109–119

    CAS  PubMed  Google Scholar 

  97. Gerhart DZ et al (1997) Expression of monocarboxylate transporter MCT1 by brain endothelium and glia in adult and suckling rats. Am J Physiol 273(1 Pt 1):E207–E213

    CAS  PubMed  Google Scholar 

  98. Lengacher S et al (2013) Resistance to diet-induced obesity and associated metabolic perturbations in haploinsufficient monocarboxylate transporter 1 mice. PLoS ONE 8(12):e82505

    PubMed  PubMed Central  Google Scholar 

  99. Merezhinskaya N et al (2000) Mutations in MCT1 cDNA in patients with symptomatic deficiency in lactate transport. Muscle Nerve 23(1):90–97

    CAS  PubMed  Google Scholar 

  100. Wang J et al (2019) Brain endothelial cells maintain lactate homeostasis and control adult hippocampal neurogenesis. Cell Stem Cell 25(6):754–767

    CAS  PubMed  Google Scholar 

  101. Liu Z et al (2016) Regulation of monocarboxylic acid transporter 1 trafficking by the canonical Wnt/β-catenin pathway in rat brain endothelial cells requires cross-talk with notch signaling. J Biol Chem 291(15):8059–8069

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Tang X et al (2017) Effect of nitric oxide to axonal degeneration in multiple sclerosis via downregulating monocarboxylate transporter 1 in oligodendrocytes. Nitric Oxide 67:75–80

    CAS  PubMed  Google Scholar 

  103. Liu S et al (2017) miR-219 attenuates demyelination in cuprizone-induced demyelinated mice by regulating monocarboxylate transporter 1. Eur J Neurosci 45(2):249–259

    PubMed  Google Scholar 

  104. Fünfschilling U et al (2012) Glycolytic oligodendrocytes maintain myelin and long-term axonal integrity. Nature 485(7399):517–521

    PubMed  PubMed Central  Google Scholar 

  105. Domènech-Estévez E et al (2015) Distribution of monocarboxylate transporters in the peripheral nervous system suggests putative roles in lactate shuttling and myelination. J Neurosci 35(10):4151–4156

    PubMed  PubMed Central  Google Scholar 

  106. Jha MK et al (2020) Monocarboxylate transporter 1 in Schwann cells contributes to maintenance of sensory nerve myelination during aging. Glia 68(1):161–177

    PubMed  Google Scholar 

  107. Morrison BM et al (2015) Deficiency in monocarboxylate transporter 1 (MCT1) in mice delays regeneration of peripheral nerves following sciatic nerve crush. Exp Neurol 263:325–338

    CAS  PubMed  Google Scholar 

  108. Bouçanova, F., et al., Disrupted function of lactate transporter MCT1, but not MCT4, in Schwann cells affects the maintenance of motor end-plate innervation. Glia, 2020.

  109. Pang R et al (2020) The distribution and density of monocarboxylate transporter 2 in cerebral cortex, hippocampus and cerebellum of wild-type mice. J Anat 236(2):370–377

    CAS  PubMed  Google Scholar 

  110. Pierre K, Pellerin L (2005) Monocarboxylate transporters in the central nervous system: distribution, regulation and function. J Neurochem 94(1):1–14

    CAS  PubMed  Google Scholar 

  111. Mason S (2017) Lactate shuttles in neuroenergetics-homeostasis, allostasis and beyond. Front Neurosci 11:43

    PubMed  PubMed Central  Google Scholar 

  112. Haydon PG, Carmignoto G (2006) Astrocyte control of synaptic transmission and neurovascular coupling. Physiol Rev 86(3):1009–1031

    CAS  PubMed  Google Scholar 

  113. Netzahualcoyotzi C, Pellerin L (2020) Neuronal and astroglial monocarboxylate transporters play key but distinct roles in hippocampus-dependent learning and memory formation. Prog Neurobiol 194:101888

    CAS  PubMed  Google Scholar 

  114. Serrano-Pozo A et al (2011) Neuropathological alterations in Alzheimer disease. Cold Spring Harb Perspect Med 1(1):a006189

    PubMed  PubMed Central  Google Scholar 

  115. Pedros I et al (2016) Molecular links between early energy metabolism alterations and Alzheimer’s disease. Front Biosci (Landmark Ed) 21:8–19

    CAS  Google Scholar 

  116. Hong P et al (2020) Role of monocarboxylate transporter 4 in Alzheimer disease. Neurotoxicology 76:191–199

    CAS  PubMed  Google Scholar 

  117. Lok K et al (2013) Characterization of the APP/PS1 mouse model of Alzheimer’s disease in senescence accelerated background. Neurosci Lett 557(Pt B):84–89

    CAS  PubMed  Google Scholar 

  118. Park SJ et al (2018) An overview of MCT1 and MCT4 in GBM: small molecule transporters with large implications. Am J Cancer Res 8(10):1967–1976

    CAS  PubMed  PubMed Central  Google Scholar 

  119. Miranda-Gonçalves V et al (2016) Hypoxia-mediated upregulation of MCT1 expression supports the glycolytic phenotype of glioblastomas. Oncotarget 7(29):46335–46353

    PubMed  PubMed Central  Google Scholar 

  120. Lai SW et al (2020) Monocarboxylate transporter 4 regulates glioblastoma motility and monocyte binding ability. Cancers (Basel) 12(2):380

    CAS  Google Scholar 

  121. Miranda-Gonçalves V et al (2017) Monocarboxylate transporter 1 is a key player in glioma-endothelial cell crosstalk. Mol Carcinog 56(12):2630–2642

    PubMed  Google Scholar 

  122. Takada T, Takata K, Ashihara E (2016) Inhibition of monocarboxylate transporter 1 suppresses the proliferation of glioblastoma stem cells. J Physiol Sci 66(5):387–396

    CAS  PubMed  Google Scholar 

  123. Lim KS et al (2014) Inhibition of monocarboxylate transporter-4 depletes stem-like glioblastoma cells and inhibits HIF transcriptional response in a lactate-independent manner. Oncogene 33(35):4433–4441

    CAS  PubMed  Google Scholar 

  124. Ganguli M et al (1996) Association between dementia and elevated TSH: a community-based study. Biol Psychiatry 40(8):714–725

    CAS  PubMed  Google Scholar 

  125. Joffe RT, Sokolov ST (1994) Thyroid hormones, the brain, and affective disorders. Crit Rev Neurobiol 8(1–2):45–63

    CAS  PubMed  Google Scholar 

  126. Scanlan TS et al (2004) 3-Iodothyronamine is an endogenous and rapid-acting derivative of thyroid hormone. Nat Med 10(6):638–642

    CAS  PubMed  Google Scholar 

  127. Friesema EC et al (2006) Thyroid hormone transport by the human monocarboxylate transporter 8 and its rate-limiting role in intracellular metabolism. Mol Endocrinol 20(11):2761–2772

    CAS  PubMed  Google Scholar 

  128. Visser WE et al (2008) Thyroid hormone transport in and out of cells. Trends Endocrinol Metab 19(2):50–56

    CAS  PubMed  Google Scholar 

  129. Mariotta L et al (2012) T-type amino acid transporter TAT1 (Slc16a10) is essential for extracellular aromatic amino acid homeostasis control. J Physiol 590(24):6413–6424

    CAS  PubMed  PubMed Central  Google Scholar 

  130. Schwartz CE et al (2005) Allan-Herndon-Dudley syndrome and the monocarboxylate transporter 8 (MCT8) gene. Am J Hum Genet 77(1):41–53

    CAS  PubMed  PubMed Central  Google Scholar 

  131. Remerand G et al (2019) Expanding the phenotypic spectrum of Allan-Herndon-Dudley syndrome in patients with SLC16A2 mutations. Dev Med Child Neurol 61(12):1439–1447

    PubMed  Google Scholar 

  132. López-Espíndola D et al (2014) Mutations of the thyroid hormone transporter MCT8 cause prenatal brain damage and persistent hypomyelination. J Clin Endocrinol Metab 99(12):E2799–E2804

    PubMed  PubMed Central  Google Scholar 

  133. Bernal J (2006) Role of monocarboxylate anion transporter 8 (MCT8) in thyroid hormone transport: answers from mice. Endocrinology 147(9):4034–4035

    CAS  PubMed  Google Scholar 

  134. Trajkovic M et al (2007) Abnormal thyroid hormone metabolism in mice lacking the monocarboxylate transporter 8. J Clin Invest 117(3):627–635

    CAS  PubMed  PubMed Central  Google Scholar 

  135. Mayerl S et al (2014) Transporters MCT8 and OATP1C1 maintain murine brain thyroid hormone homeostasis. J Clin Invest 124(5):1987–1999

    CAS  PubMed  PubMed Central  Google Scholar 

  136. Mayerl S et al (2012) Impact of Oatp1c1 deficiency on thyroid hormone metabolism and action in the mouse brain. Endocrinology 153(3):1528–1537

    CAS  PubMed  Google Scholar 

  137. van Mullem AA et al (2016) Effects of thyroid hormone transporters MCT8 and MCT10 on nuclear activity of T3. Mol Cell Endocrinol 437:252–260

    PubMed  Google Scholar 

  138. Betz AL et al (1994) Blood-brain barrier permeability and brain concentration of sodium, potassium, and chloride during focal ischemia. J Cereb Blood Flow Metab 14(1):29–37

    CAS  PubMed  Google Scholar 

  139. Hawkins RA et al (2013) Synergism between the two membranes of the blood–brain barrier: glucose and amino acid transport. Am J Neurosci Res 1:1–25

    Google Scholar 

  140. Nalecz KA (2017) Solute Carriers in the Blood-Brain Barier: Safety in Abundance. Neurochem Res 42(3):795–809

    CAS  PubMed  Google Scholar 

  141. Sanchez del Pino MM, Peterson DR, Hawkins RA (1995) Neutral amino acid transport characterization of isolated: luminal and abluminal membranes of the blood-brain barrier. J Biol Chem 270(25):14913–14918

    CAS  PubMed  Google Scholar 

  142. Sánchez-Campillo M et al (2019) Decreased blood level of MFSD2a as a potential biomarker of Alzheimer’s disease. Int J Mol Sci 21(1):70–70

    PubMed Central  Google Scholar 

  143. Duelli R et al (2000) Expression of large amino acid transporter LAT1 in rat brain endothelium. J Cereb Blood Flow Metab 20(11):1557–1562

    CAS  PubMed  Google Scholar 

  144. Kanai Y et al (1998) Expression cloning and characterization of a transporter for large neutral amino acids activated by the heavy chain of 4F2 antigen (CD98). J Biol Chem 273(37):23629–23632

    CAS  PubMed  Google Scholar 

  145. Nakamura E et al (1999) 4F2 (CD98) heavy chain is associated covalently with an amino acid transporter and controls intracellular trafficking and membrane topology of 4F2 heterodimer. J Biol Chem 274(5):3009–3016

    CAS  PubMed  Google Scholar 

  146. Prasad, P.D., et al., Human LAT1, a Subunit of System L Amino Acid Transporter: Molecular Cloning and Transport Function 1. 1999.

  147. Segawa H et al (1999) Identification and functional characterization of a Na+-independent neutral amino acid transporter with broad substrate selectivity*. J Biol Chem. https://doi.org/10.1074/jbc.274.28.19745

    Article  PubMed  Google Scholar 

  148. Kanai Y et al (1998) Expression cloning and characterization of a transporter for large neutral amino acids activated by the heavy chain of 4F2 antigen (CD98)*. J Biol Chem. https://doi.org/10.1074/jbc.273.37.23629

    Article  PubMed  Google Scholar 

  149. Mastroberardino L et al (1998) Amino-acid transport by heterodimers of 4F2hc/CD98 and members of a permease family. Nature. https://doi.org/10.1038/26246

    Article  PubMed  Google Scholar 

  150. Meier C (2002) Activation of system L heterodimeric amino acid exchangers by intracellular substrates. EMBO J 21(4):580–589

    CAS  PubMed  PubMed Central  Google Scholar 

  151. Geier EG et al (2013) Structure-based ligand discovery for the large-neutral amino acid transporter 1 LAT-1. Proc Natl Acad Sci USA 110:5480–5485

    CAS  PubMed  PubMed Central  Google Scholar 

  152. Napolitano L et al (2017) Novel insights into the transport mechanism of the human amino acid transporter LAT1 (SLC7A5) Probing critical residues for substrate translocation. Biochim Biophys Acta. https://doi.org/10.1016/j.bbagen.2017.01.013

    Article  Google Scholar 

  153. Fotiadis D, Kanai Y, Palacín M (2013) The SLC3 and SLC7 families of amino acid transporters. Mol Aspects Med 34:139–158

    CAS  PubMed  Google Scholar 

  154. Singh N, Ecker GF (2018) Insights into the structure, function, and ligand discovery of the large neutral amino acid transporter 1, lat1. Int J Mol Sci 19:1278

    PubMed Central  Google Scholar 

  155. Tărlungeanu DC et al (2016) Impaired amino acid transport at the blood brain barrier is a cause of autism spectrum disorder. Cell 167(6):1481–1494

    PubMed  PubMed Central  Google Scholar 

  156. Poncet N et al (2014) LAT1 (Slc7a5) null mice are embryonic lethal and exhibit neural tube defects (8965). FASEB J 28(S1):896

    Google Scholar 

  157. Ohtsuki S et al (2010) Reduction of L-type amino acid transporter 1 mRNA expression in brain capillaries in a mouse model of Parkinson’s disease. Biol Pharm Bull 33:1250–1252

    CAS  PubMed  Google Scholar 

  158. Stoll J, Wadhwani KC, Smith QR (1993) Identification of the cationic amino acid transporter (System y+) of the rat blood–brain barrier. J Neurochem 60(5):1956–1959

    CAS  PubMed  Google Scholar 

  159. Closs EI et al (2006) Structure and function of cationic amino acid transporters (CATs). Springer, Berlin, pp 67–77

    Google Scholar 

  160. Devés R, Boyd CAR (1989) Transporters for cationic amino acids in animal cells: discovery, structure, and function. American Physiological Society, Rockville, pp 487–545

    Google Scholar 

  161. Wang H, Kavanaugh MP, Kabat D (1994) A critical site in the cell surface receptor for ecotropic murine retroviruses required for amino acid transport but not for viral reception. Virology 202(2):1058–1060

    CAS  PubMed  Google Scholar 

  162. O’Kane RL et al (2006) Cationic amino acid transport across the blood-brain barrier is mediated exclusively by system y+. Am J Physiol Endocrinol Metab. https://doi.org/10.1152/ajpendo.00007.2006291(2)

    Article  PubMed  Google Scholar 

  163. Perkins CP et al (1997) Anemia and perinatal death result from loss of the murine ecotropic retrovirus receptor mCAT-1. Genes Dev 11(7):914–925

    CAS  PubMed  Google Scholar 

  164. Bridges RJ, Natale NR, Patel SA (2012) System x c-cystine/glutamate antiporter: an update on molecular pharmacology and roles within the CNS. Wiley, New York, pp 20–34

    Google Scholar 

  165. Conrad M, Sato H (2012) The oxidative stress-inducible cystine/glutamate antiporter, system x c-: cystine supplier and beyond. Springer, Berlin

    Google Scholar 

  166. Sato H et al (1999) Cloning and expression of a plasma membrane cystine/glutamate exchange transporter composed of two distinct proteins. J Biol Chem 274(17):11455–11458

    CAS  PubMed  Google Scholar 

  167. Fagerberg L et al (2014) Analysis of the human tissue-specific expression by genome-wide integration of transcriptomics and antibody-based proteomics. Mol Cell Proteomics 13(2):397–406

    CAS  PubMed  Google Scholar 

  168. Burdo J, Dargusch R, Schubert D (2006) Distribution of the cystine/glutamate antiporter system xc- in the brain, kidney, and duodenum. J Histochem Cytochem 54(5):549–557

    CAS  PubMed  Google Scholar 

  169. Bannai S et al (1986) Induction of cystine transport activity in isolated rat hepatocytes by sulfobromophthalein and other electrophilic agents. Hepatology 6(6):1361–1368

    CAS  PubMed  Google Scholar 

  170. Watanabe H, Bannai S (1987) Induction of cystine transport activity in mouse peritoneal macrophages. J Exp Med 165(3):628–640

    CAS  PubMed  Google Scholar 

  171. Nabeyama A et al (2010) xCT deficiency accelerates chemically induced tumorigenesis. Proc Natl Acad Sci USA 107(14):6436–6441

    CAS  PubMed  PubMed Central  Google Scholar 

  172. de Bundel D et al (2011) Loss of system xc- does not induce oxidative stress but decreases extracellular glutamate in hippocampus and influences spatial working memory and limbic seizure susceptibility. J Neurosci 31(15):5792–5803

    PubMed  PubMed Central  Google Scholar 

  173. Zaragozá R (2020) Transport of amino acids across the blood-brain barrier. Front Physiol 11:973–973

    PubMed  PubMed Central  Google Scholar 

  174. Takanaga H et al (2005) Characterization of a branched-chain amino-acid transporter SBAT1 (SLC6A15) that is expressed in human brain. Biochem Biophys Res Commun 337(3):892–900

    CAS  PubMed  Google Scholar 

  175. Melikian HE (2004) Neurotransmitter transporter trafficking: endocytosis, recycling, and regulation. Pharmacol Ther 104(1):17–27

    CAS  PubMed  Google Scholar 

  176. Sakai R et al (2004) Leucine-nitrogen metabolism in the brain of conscious rats: its role as a nitrogen carrier in glutamate synthesis in glial and neuronal metabolic compartments. J Neurochem 88(3):612–622

    CAS  PubMed  Google Scholar 

  177. Drgonova J et al (2007) Deletion of v7–3 (SLC6A15) transporter allows assessment of its roles in synaptosomal proline uptake, leucine uptake and behaviors. Brain Res 1183(1):10–20

    CAS  PubMed  PubMed Central  Google Scholar 

  178. Hägglund MGA et al (2013) B0AT2 (SLC6A15) is localized to neurons and astrocytes, and is involved in mediating the effect of leucine in the brain. PLoS ONE 8(3):e58651

    PubMed  PubMed Central  Google Scholar 

  179. Nałęcz KA (2017) solute carriers in the blood–brain barier: safety in abundance. Neurochem Res 42(3):795–809

    PubMed  Google Scholar 

  180. Hatanaka T et al (2000) Primary structure, functional characteristics and tissue expression pattern of human ATA2, a subtype of amino acid transport system A. Biochim Biophys Acta 1467(1):1–6

    CAS  PubMed  Google Scholar 

  181. Lee WJ et al (1998) Glutamine transport by the blood-brain barrier: a possible mechanism for nitrogen removal. Am J Physiol 274:43–44

    Google Scholar 

  182. Menchini RJ, Chaudhry FA (2019) Multifaceted regulation of the system A transporter Slc38a2 suggests nanoscale regulation of amino acid metabolism and cellular signaling. Elsevier, Amsterdam, p 107789

    Google Scholar 

  183. Ruderisch N et al (2011) Differential axial localization along the mouse brain vascular tree of luminal sodium-dependent glutamine transporters Snat1 and Snat3. J Cereb Blood Flow Metab 31(7):1637–1647

    CAS  PubMed  PubMed Central  Google Scholar 

  184. O’Kane RL et al (2004) Na+-dependent neutral amino acid transporters A, ASC, and N of the blood-brain barrier: mechanisms for neutral amino acid removal. Am J Physiol Endocrinol Metab 287(4):E622–E629

    CAS  PubMed  Google Scholar 

  185. Yamada D et al (2019) Inhibition of the glutamine transporter SNAT1 confers neuroprotection in mice by modulating the mTOR-autophagy system. Commun Biol 2(1):1–11

    CAS  Google Scholar 

  186. Papadakis M et al (2013) Tsc1 (hamartin) confers neuroprotection against ischemia by inducing autophagy. Nat Med 19(3):351–357

    CAS  PubMed  PubMed Central  Google Scholar 

  187. Nixon RA (2013) The role of autophagy in neurodegenerative disease. Nature Publishing Group, Berlin, pp 983–997

    Google Scholar 

  188. Nakajo T et al (2004) Glutamine is a key regulator for amino acid-controlled cell growth through the mTOR signaling pathway in rat intestinal epithelial cells. Biochem Biophys Res Commun 326(1):174–180

    Google Scholar 

  189. O’Kane RL et al (1999) Na+-dependent glutamate transporters (EAAT1, EAAT2, and EAAT3) of the blood-brain barrier. A mechanism for glutamate removal. J Biol Chem 274(45):31891–31895

    CAS  PubMed  Google Scholar 

  190. Hans Christian Cederberg H, Carsten Uhd N, Brodin B (2014) Glutamate efflux at the blood-brain barrier: cellular mechanisms and potential clinical relevance. Elsevier, Amsterdam, pp 639–645

    Google Scholar 

  191. Jl A et al (1994) Functional comparisons of three glutamate transporter subtypes cloned from human motor cortex. J Neurosci 14(9):5559–5569

    Google Scholar 

  192. O’Kane RL, Hawkins RA (2003) Na+-dependent transport of large neutral amino acids occurs at the abluminal membrane of the blood–brain barrier. Am J Physiol Endocrinol Metab 285:48–66

    Google Scholar 

  193. O’Donovan SM, Sullivan CR, McCullumsmith RE (2017) The role of glutamate transporters in the pathophysiology of neuropsychiatric disorders. NPJ Schizophr 3(1):32–32

    PubMed  PubMed Central  Google Scholar 

  194. Chan JP et al (2018) The lysolipid transporter Mfsd2a regulates lipogenesis in the developing brain. PLoS Biol 16(8):1–30

    Google Scholar 

  195. Parkin GM et al (2018) Glutamate transporters, EAAT1 and EAAT2, are potentially important in the pathophysiology and treatment of schizophrenia and affective disorders. World J Psychiatry 8(2):51–51

    PubMed  PubMed Central  Google Scholar 

  196. O’Brien JS, Fillerup DL, Mead JF (1964) Brain lipids: I. Quantification and fatty acid composition of. J Lipid Res 15:109–116

    Google Scholar 

  197. Aa F et al (2007) Comparison of biochemical effects of statins and fish oil in brain: the battle of the titans. Brain Res Rev 56(2):443–471

    Google Scholar 

  198. Hansen HS, Artmann A (2008) Endocannabinoids and Nutrition. J Neuroendocrinol 20(Suppl 1):94–99

    CAS  PubMed  Google Scholar 

  199. Tan ST et al (2020) (2020) Emerging roles of lysophospholipids in health and disease. Prog Lipid Res 80:101068

    CAS  PubMed  Google Scholar 

  200. Nguyen LN et al (2014) Mfsd2a is a transporter for the essential omega-3 fatty acid docosahexaenoic acid. Nature 509(7501):503–506

    CAS  PubMed  Google Scholar 

  201. Ben-Zvi A et al (2014) Mfsd2a is critical for the formation and function of the blood–brain barrier. Nature 509:507–511

    CAS  PubMed  PubMed Central  Google Scholar 

  202. Quek DQY et al (2016) Structural insights into the transport mechanism of the human sodium-dependent lysophosphatidylcholine transporter MFSD2A. J Biol Chem 291(18):9383–9394

    CAS  PubMed  PubMed Central  Google Scholar 

  203. Cater RJ et al (2021) Structural basis of omega-3 fatty acid transport across the blood–brain barrier. Nature 595:315–319

    CAS  PubMed  PubMed Central  Google Scholar 

  204. Andreone BJ et al (2017) Blood–brain barrier permeability is regulated by lipid transport-dependent suppression of caveolae-mediated transcytosis. Neuron. https://doi.org/10.1016/j.neuron.2017.03.043

    Article  PubMed  PubMed Central  Google Scholar 

  205. Andaloussi Mae M et al (2020) Single-cell analysis of blood–brain barrier response to pericyte loss. Circ Res. https://doi.org/10.1161/CIRCRESAHA.120.317473

    Article  Google Scholar 

  206. Wong BH et al (2016) mfsd2a is a transporter for the essential omega-3 fatty acid docosahexaenoic acid (DHA) in eye and is important for photoreceptor cell development. J Biol Chem 291(20):10501–10514

    CAS  PubMed  PubMed Central  Google Scholar 

  207. Alakbarzade V et al (2015) A partially inactivating mutation in the sodium-dependent lysophosphatidylcholine transporter MFSD2A causes a non-lethal microcephaly syndrome. Nat Genet 47(7):814–817

    CAS  PubMed  Google Scholar 

  208. Guemez-Gamboa A et al (2015) Inactivating mutations in MFSD2A, required for omega-3 fatty acid transport in brain, cause a lethal microcephaly syndrome. Nat Genet 47:809–813

    CAS  PubMed  PubMed Central  Google Scholar 

  209. Harel T et al (2018) Homozygous mutation in MFSD2A, encoding a lysolipid transporter for docosahexanoic acid, is associated with microcephaly and hypomyelination. Neurogenetics 19(4):227–235

    PubMed  Google Scholar 

  210. Sugasini D et al (2017) Dietary docosahexaenoic acid (DHA) as lysophosphatidylcholine, but not as free acid, enriches brain DHA and improves memory in adult mice. Sci Rep 7(1):1–11

    CAS  Google Scholar 

  211. Brenna JT, Carlson SE (2014) Docosahexaenoic acid and human brain development: evidence that adietary supply is needed for optimal development. J Hum Evol 77:99–106

    PubMed  Google Scholar 

  212. Olson CR, Mello CV (2010) Significance of vitamin A to brain function, behavior and learning. Mol Nutr Food Res 54(4):489–495

    CAS  PubMed  PubMed Central  Google Scholar 

  213. Zhang J et al (2021) Vitamin E deficiency dysregulates thiols, amino acids and related molecules during zebrafish embryogenesis. Redox Biol 38:101784

    CAS  PubMed  Google Scholar 

  214. Zhong M et al (2013) Vitamin A transport and the transmembrane pore in the cell-surface receptor for plasma retinol binding protein. PLoS ONE 8(11):e73838

    CAS  PubMed  PubMed Central  Google Scholar 

  215. Chen Y et al (2016) Structure of the STRA6 receptor for retinol uptake. Science 353:6302

    Google Scholar 

  216. Kelly M et al (2016) Transport of vitamin A across blood-tissue barriers is facilitated by STRA6. FASEB J 30(8):2985–2995

    CAS  PubMed  PubMed Central  Google Scholar 

  217. Savini I et al (2008) SVCT1 and SVCT2: key proteins for vitamin C uptake. Amino Acids 34(3):347–355

    CAS  PubMed  Google Scholar 

  218. Agus DB et al (1997) Vitamin C crosses the blood-brain barrier in the oxidized form through the glucose transporters. J Clin Invest 100(11):2842–2848

    CAS  PubMed  PubMed Central  Google Scholar 

  219. Harrison FE, May JM (2009) Vitamin C function in the brain: vital role of the ascorbate transporter SVCT2. Free Radic Biol Med 46(6):719–730

    CAS  PubMed  PubMed Central  Google Scholar 

  220. Bornstein SR et al (2003) Impaired adrenal catecholamine system function in mice with deficiency of the ascorbic acid transporter (SVCT2). FASEB J 17(13):1928–1930

    CAS  PubMed  Google Scholar 

  221. Harrison FE et al (2010) Low vitamin C and increased oxidative stress and cell death in mice that lack the sodium-dependent vitamin C transporter SVCT2. Free Radic Biol Med 49(5):821–829

    CAS  PubMed  PubMed Central  Google Scholar 

  222. Covarrubias-Pinto A et al (2020) Impaired intracellular trafficking of sodium-dependent vitamin C transporter 2 contributes to the redox imbalance in Huntington’s disease. J Neurosci Res 38:178–188

    Google Scholar 

  223. Dhir S et al (2019) Neurological, psychiatric, and biochemical aspects of thiamine deficiency in children and adults. Front Psychiatry 10:207

    PubMed  PubMed Central  Google Scholar 

  224. Manzetti S, Zhang J, van der Spoel D (2014) Thiamin function, metabolism, uptake, and transport. Biochemistry 53(5):821–835

    CAS  PubMed  Google Scholar 

  225. Greenwood J, Love ER, Pratt OE (1982) Kinetics of thiamine transport across the blood-brain barrier in the rat. J Physiol 327:95–103

    CAS  PubMed  PubMed Central  Google Scholar 

  226. Patel M et al (2012) Molecular and functional characterization of riboflavin specific transport system in rat brain capillary endothelial cells. Brain Res 1468:1–10

    CAS  PubMed  PubMed Central  Google Scholar 

  227. Mosegaard S et al (2017) An intronic variation in SLC52A1 causes exon skipping and transient riboflavin-responsive multiple acyl-CoA dehydrogenation deficiency. Mol Genet Metab 122(4):182–188

    CAS  PubMed  Google Scholar 

  228. Yao Y et al (2010) Identification and comparative functional characterization of a new human riboflavin transporter hRFT3 expressed in the brain. J Nutr 140(7):1220–1226

    CAS  PubMed  Google Scholar 

  229. Berezowski V et al (2004) Involvement of OCTN2 and B0,+ in the transport of carnitine through an in vitro model of the blood–brain barrier. J Neurochem 91(4):860–872

    CAS  PubMed  Google Scholar 

  230. Michalec K et al (2014) Protein kinase C restricts transport of carnitine by amino acid transporter ATB(0,+) apically localized in the blood-brain barrier. Arch Biochem Biophys 554:28–35

    CAS  PubMed  Google Scholar 

  231. Czeredys M et al (2008) A polarized localization of amino acid/carnitine transporter B(0,+) (ATB(0,+)) in the blood–brain barrier. Biochem Biophys Res Commun 376(2):267–270

    CAS  PubMed  Google Scholar 

  232. Okura T, Kato S, Deguchi Y (2014) Functional expression of organic cation/carnitine transporter 2 (OCTN2/SLC22A5) in human brain capillary endothelial cell line hCMEC/D3, a human blood-brain barrier model. Drug Metab Pharmacokinet 29(1):69–74

    CAS  PubMed  Google Scholar 

  233. Juraszek B, Czarnecka-Herok J, Nałęcz KA (2020) Glioma cells survival depends both on fatty acid oxidation and on functional carnitine transport by SLC22A5. J Neurochem 156:642–657

    PubMed  Google Scholar 

  234. Tucker RAJ, Cheah IK, Halliwell B (2019) Specificity of the ergothioneine transporter natively expressed in HeLa cells. Biochem Biophys Res Commun 513(1):22–27

    CAS  PubMed  Google Scholar 

  235. Koh SS et al (2021) Effect of ergothioneine on 7-ketocholesterol-induced endothelial injury. Neuromolecular Med 23(1):184–198

    CAS  PubMed  Google Scholar 

  236. Kalailingam P et al (2020) Deficiency of MFSD7c results in microcephaly-associated vasculopathy in Fowler syndrome. J Clin Invest 130(8):4081–4093

    CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This study was supported in part by Singapore Ministry of Health’s National Research Council NMRC/OFIRG/0066/20, Ministry of Education MOE2018-T2-1-126, MOE-Tier-1, and NUSMED-FOS Joint Research Programme grant on Healthy Brain Aging grants (to L.N.N.).

Funding

Government funding sources. Singapore Ministry of Health’s National Research Council NMRC/OFIRG/0066/20, Ministry of Education MOE2018-T2-1–126, MOE-Tier-1, and NUSMED-FOS Joint Research Programme grant on Healthy Brain Aging grants.

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  1. Yen T. K. Nguyen, Hoa T. T. Ha and Tra H. Nguyen contributed equally.

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  1. Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117596, Singapore

    Yen T. K. Nguyen, Hoa T. T. Ha, Tra H. Nguyen & Long N. Nguyen

  2. SLING/Immunology Program, Life Sciences Institute, National University of Singapore, Singapore, 117456, Singapore

    Long N. Nguyen

  3. Immunology Translational and Cardiovascular Disease Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117545, Singapore

    Long N. Nguyen

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Nguyen, Y.T.K., Ha, H.T.T., Nguyen, T.H. et al. The role of SLC transporters for brain health and disease. Cell. Mol. Life Sci. 79, 20 (2022). https://doi.org/10.1007/s00018-021-04074-4

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