scholarly journals A Proton-Coupled Transport System for β-Hydroxy-β-Methylbutyrate (HMB) in Blood–Brain Barrier Endothelial Cell Line hCMEC/D3

Nutrients ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 3220
Author(s):  
Kei Higuchi ◽  
Sathish Sivaprakasam ◽  
Souad R. Sennoune ◽  
Jiro Ogura ◽  
Yangzom D. Bhutia ◽  
...  
Keyword(s):  
Endothelial Cell ◽  
Amino Acid ◽  
Gene Family ◽  
Cell Line ◽  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Monocarboxylate Transporter ◽  
Endothelial Cell Line ◽  
Solute Carrier ◽  
The Brain

β-Hydroxy-β-methylbutyrate (HMB), a leucine metabolite, is used as a nutritional ingredient to improve skeletal muscle health. Preclinical studies indicate that this supplement also elicits significant benefits in the brain; it promotes neurite outgrowth and prevents age-related reductions in neuronal dendrites and cognitive performance. As orally administered HMB elicits these effects in the brain, we infer that HMB crosses the blood–brain barrier (BBB). However, there have been no reports detailing the transport mechanism for HMB in BBB. Here we show that HMB is taken up in the human BBB endothelial cell line hCMEC/D3 via H+-coupled monocarboxylate transporters that also transport lactate and β-hydroxybutyrate. MCT1 (monocarboxylate transporter 1) and MCT4 (monocarboxylate transporter 4) belonging to the solute carrier gene family SLC16 (solute carrier, gene family 16) are involved, but additional transporters also contribute to the process. HMB uptake in BBB endothelial cells results in intracellular acidification, demonstrating cotransport with H+. Since HMB is known to activate mTOR with potential to elicit transcriptomic changes, we examined the influence of HMB on the expression of selective transporters. We found no change in MCT1 and MCT4 expression. Interestingly, the expression of LAT1 (system L amino acid transporter 1), a high-affinity transporter for branched-chain amino acids relevant to neurological disorders such as autism, is induced. This effect is dependent on mTOR (mechanistic target of rapamycine) activation by HMB with no involvement of histone deacetylases. These studies show that HMB in systemic circulation can cross the BBB via carrier-mediated processes, and that it also has a positive influence on the expression of LAT1, an important amino acid transporter in the BBB.

Development of immortalized human cerebromicrovascular endothelial cell line as an in vitro model of the human blood–brain barrier

1997 ◽  
Vol 11 (13) ◽  
pp. 1187-1197 ◽  
Author(s):  
Arumugam Muruganandam ◽  
Leonie Moorhouse Herx ◽  
Robert Monette ◽  
Jon P. Durkin ◽  
Danica B. Stanimirovic
Keyword(s):  
Endothelial Cell ◽  
Cell Line ◽  
Blood Brain Barrier ◽  
Human Blood ◽  
In Vitro Model ◽  
Brain Barrier ◽  
Endothelial Cell Line ◽  
Blood Brain ◽  
Vitro Model

scholarly journals Asymmetrical Transport of Amino Acids across the Blood—Brain Barrier in Humans

1990 ◽  
Vol 10 (5) ◽  
pp. 698-706 ◽  
Author(s):  
G. Moos Knudsen ◽  
K. D. Pettigrew ◽  
C. S. Patlak ◽  
M. M. Hertz ◽  
O. B. Paulson
Keyword(s):  
Amino Acids ◽  
Endothelial Cell ◽  
Amino Acid ◽  
Blood Brain Barrier ◽  
Extracellular Fluid ◽  
Brain Barrier ◽  
Reverse Direction ◽  
Single Membrane ◽  
Blood Brain ◽  
The Brain

Blood–brain barrier permeability to four large neutral and one basic amino acid was studied in 30 patients with the double indicator technique. The resultant 64 venous outflow curves were analyzed by means of two models that take tracer backflux and capillary heterogeneity into account. The first model considers the blood–brain barrier as a double membrane where amino acids from plasma enter the endothelial cell. When an endothelial cell volume of 0.001 ml/g was assumed, permeability from the blood into the endothelial cell was, for most amino acids, about 10–20 times larger than the permeability for the reverse direction. The second model assumes that the amino acids, after intracarotid injection, cross a single membrane barrier and enter a well-mixed compartment, the brain extracellular fluid, i.e., the endothelial cell is assumed to behave as a single membrane. With this model, for large neutral amino acids, the permeability out of the extracellular fluid space back to the blood was between 8 to 12 times higher than the permeability from the blood into the brain. Such a difference in permeabilities across the blood–brain barrier can almost entirely be ascribed to the effect of a nonlinear transport system combined with a relatively small brain amino acid metabolism. The significance of the possible presence of an energy-dependent A system at the abluminal side of the blood–brain barrier is discussed and related to the present findings. For both models, calculation of brain extraction by simple peak extraction values underestimates true unidirectional brain uptake by 17–40%. This raises methodological problems when estimating blood to brain transfer of amino acids with this traditional in vivo method.

Induction of Blood-Brain Barrier Differentiation in a Rat Brain-Derived Endothelial Cell Line

1995 ◽  
Vol 220 (1) ◽  
pp. 161-170 ◽  
Author(s):  
Delphine Lechardeur ◽  
Bertrand Schwartz ◽  
Denise Paulin ◽  
Daniel Scherman
Keyword(s):  
Endothelial Cell ◽  
Rat Brain ◽  
Cell Line ◽  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Endothelial Cell Line ◽  
Blood Brain

scholarly journals Blood‐brain barrier‐specific properties of a human adult brain endothelial cell line

2005 ◽  
Vol 19 (13) ◽  
pp. 1872-1874 ◽  
Author(s):  
B. B. Weksler ◽  
E. A. Subileau ◽  
N. Perrière ◽  
P. Charneau ◽  
K. Holloway ◽  
...  
Keyword(s):  
Endothelial Cell ◽  
Cell Line ◽  
Blood Brain Barrier ◽  
Adult Brain ◽  
Brain Barrier ◽  
Brain Endothelial Cell ◽  
Endothelial Cell Line ◽  
Human Adult ◽  
Blood Brain

scholarly journals Purine receptors and Ca2+ signalling in the human blood–brain barrier endothelial cell line hCMEC/D3

2011 ◽  
Vol 8 (1) ◽  
pp. 71-80 ◽  
Author(s):  
Willem Bintig ◽  
Daniela Begandt ◽  
Barbara Schlingmann ◽  
Linda Gerhard ◽  
Maria Pangalos ◽  
...  
Keyword(s):  
Endothelial Cell ◽  
Cell Line ◽  
Blood Brain Barrier ◽  
Human Blood ◽  
Brain Barrier ◽  
Purine Receptors ◽  
Endothelial Cell Line ◽  
Blood Brain

scholarly journals In vitro models of the blood–brain barrier: An overview of commonly used brain endothelial cell culture models and guidelines for their use

2016 ◽  
Vol 36 (5) ◽  
pp. 862-890 ◽  
Author(s):  
Hans C Helms ◽  
N Joan Abbott ◽  
Malgorzata Burek ◽  
Romeo Cecchelli ◽  
Pierre-Olivier Couraud ◽  
...  
Keyword(s):  
Cell Culture ◽  
Endothelial Cell ◽  
Blood Brain Barrier ◽  
Brain Parenchyma ◽  
Brain Barrier ◽  
Blood Brain ◽  
Culture Models ◽  
Cell Culture Models ◽  
The Brain

The endothelial cells lining the brain capillaries separate the blood from the brain parenchyma. The endothelial monolayer of the brain capillaries serves both as a crucial interface for exchange of nutrients, gases, and metabolites between blood and brain, and as a barrier for neurotoxic components of plasma and xenobiotics. This “blood-brain barrier” function is a major hindrance for drug uptake into the brain parenchyma. Cell culture models, based on either primary cells or immortalized brain endothelial cell lines, have been developed, in order to facilitate in vitro studies of drug transport to the brain and studies of endothelial cell biology and pathophysiology. In this review, we aim to give an overview of established in vitro blood–brain barrier models with a focus on their validation regarding a set of well-established blood–brain barrier characteristics. As an ideal cell culture model of the blood–brain barrier is yet to be developed, we also aim to give an overview of the advantages and drawbacks of the different models described.

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