The Blood Brain Barrier — Regulation of Fatty Acid and Drug Transport

Dalvi, Siddhartha; On, Ngoc; Nguyen, Hieu; Pogorzelec, Donald W. Miller Michael; Hatch, Grant M.

doi:10.5772/57604

Cited by 19 publications

(26 citation statements)

References 151 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…In addition, the cells used in our study lack interaction with other cells of the BBB including pericytes and astrocyte foot processes (Gumbleton and Audus ; Dalvi et al . ). Thus, the changes observed in permeability of glucose caused by reduced CL may be underestimated in this study.…”

Section: Discussionmentioning

confidence: 97%

Reduction in cardiolipin decreases mitochondrial spare respiratory capacity and increases glucose transport into and across human brain cerebral microvascular endothelial cells

Nguyen

Mejia

Chang

et al. 2016

Journal of Neurochemistry

Self Cite

View full text Add to dashboard Cite

Microvessel endothelial cells form part of the blood-brain barrier, a restrictively permeable interface that allows transport of only specific compounds into the brain. Cardiolipin is a mitochondrial phospholipid required for function of the electron transport chain and ATP generation. We examined the role of cardiolipin in maintaining mitochondrial function necessary to support barrier properties of brain microvessel endothelial cells. Knockdown of the terminal enzyme of cardiolipin synthesis, cardiolipin synthase, in hCMEC/D3 cells resulted in decreased cellular cardiolipin levels compared to controls. The reduction in cardiolipin resulted in decreased mitochondrial spare respiratory capacity, increased pyruvate kinase activity, and increased 2-deoxy-[(3) H]glucose uptake and glucose transporter-1 expression and localization to membranes in hCMEC/D3 cells compared to controls. The mechanism for the increase in glucose uptake was an increase in adenosine-5'-monophosphate kinase and protein kinase B activity and decreased glycogen synthase kinase 3 beta activity. Knockdown of cardiolipin synthase did not affect permeability of fluorescent dextran across confluent hCMEC/D3 monolayers grown on Transwell(®) inserts. In contrast, knockdown of cardiolipin synthase resulted in an increase in 2-deoxy-[(3) H]glucose transport across these monolayers compared to controls. The data indicate that in hCMEC/D3 cells, spare respiratory capacity is dependent on cardiolipin. In addition, reduction in cardiolipin in these cells alters their cellular energy status and this results in increased glucose transport into and across hCMEC/D3 monolayers. Microvessel endothelial cells form part of the blood-brain barrier, a restrictively permeable interface that allows transport of only specific compounds into the brain. In human adult brain endothelial cell hCMEC/D3 monolayers cultured on Transwell(®) plates, knockdown of cardiolipin synthase results in decrease in mitochondrial cardiolipin and decreased mitochondrial spare respiratory capacity. The reduced cardiolipin results in an increased activity of adenosine monophosphate kinase (pAMPK) and protein kinase B (pAKT) and decreased activity of glycogen synthase kinase 3 beta (pGSK3β) which results in elevated glucose transporter-1 (GLUT-1) expression and association with membranes. This in turn increases 2-dexoyglucose uptake from the apical medium into the cells with a resultant 2-deoxyglucose movement into the basolateral medium.

show abstract

Section: Discussionmentioning

confidence: 97%

Reduction in cardiolipin decreases mitochondrial spare respiratory capacity and increases glucose transport into and across human brain cerebral microvascular endothelial cells

Nguyen

Mejia

Chang

et al. 2016

Journal of Neurochemistry

Self Cite

View full text Add to dashboard Cite

show abstract

“…It is comprised of microvessel endothelial cells, astrocyte foot processes and pericytes. The selective permeability of the BBB is mediated by the microvessel endothelium, which regulates both the transcellular and paracellular movement of molecules into the brain [1][2][3][4][5]. In addition to a physical barrier, the BBB serves as a metabolic barrier, and its integrity is critical in maintaining homeostasis of the microenvironment of the brain [6].…”

Section: Introductionmentioning

confidence: 99%

“…The human blood-brain barrier (BBB) is the selectively permeable barrier that separates the brain parenchyma and the circulating blood [1,2]. It is comprised of microvessel endothelial cells, astrocyte foot processes and pericytes.…”

Section: Introductionmentioning

confidence: 99%

Generation of Bioactive Oxylipins from Exogenously Added Arachidonic, Eicosapentaenoic and Docosahexaenoic Acid in Primary Human Brain Microvessel Endothelial Cells

Aukema

Winter

Ravandi

et al. 2015

Lipids

Self Cite

View full text Add to dashboard Cite

The human blood-brain barrier (BBB) is the restrictive barrier between the brain parenchyma and the circulating blood and is formed in part by microvessel endothelial cells. The brain contains significant amounts of arachidonic acid (ARA), and docosahexaenoic acid (DHA), which potentially give rise to the generation of bioactive oxylipins. Oxylipins are oxygenated fatty acid metabolites that are involved in an assortment of biological functions regulating neurological health and disease. Since it is not known which oxylipins are generated by human brain microvessel endothelial cells (HBMECs), they were incubated for up to 30 min in the absence or presence of 0.1-mM ARA, eicosapentaenoic acid (EPA) or DHA bound to albumin (1:1 molar ratio), and the oxylipins generated were examined using high performance liquid chromatography-tandem mass spectrometry (HPLC/MS/MS). Of 135 oxylipins screened in the media, 63 were present at >0.1 ng/mL at baseline, and 95 were present after incubation with fatty acid. Oxylipins were rapidly generated and reached maximum levels by 2-5 min. While ARA, EPA and DHA each stimulated the production of oxylipins derived from these fatty acids themselves, ARA also stimulated the production of oxylipins from endogenous 18- and 20-carbon fatty acids, including α-linolenic acid. Oxylipins generated by the lipoxygenase pathway predominated both in resting and stimulated states. Oxylipins formed via the cytochrome P450 pathway were formed primarily from DHA and EPA, but not ARA. These data indicate that HBMECs are capable of generating a plethora of bioactive lipids that have the potential to modulate BBB endothelial cell function.

show abstract

“…Efficient transport of FAs over the blood-brain barrier was already demonstrated with 14 C labelled FAs in 1988 [5], and has been consistently observed ever since, though the mechanism(s) involved are still debated (see e.g. [6] and [7]). Lastly, the neuronal KAT indeed has very low activity, but this regulation has been established during evolution and might easily be changed, leaving the question: "what is the selective advantage of not using FA oxidation for energy generation in neurons?"…”

Section: Introductionmentioning

confidence: 99%

Evolution of peroxisomes illustrates symbiogenesis

Speijer

2017

BioEssays

View full text Add to dashboard Cite

Recently, the group of McBride reported a stunning observation regarding peroxisome biogenesis: newly born peroxisomes are hybrids of mitochondrial and ER-derived pre-peroxisomes. What was stunning? Studies performed with the yeast Saccharomyces cerevisiae had convincingly shown that peroxisomes are ER-derived, without indications for mitochondrial involvement. However, the recent finding using fibroblasts dovetails nicely with a mechanism inferred to be driving the eukaryotic invention of peroxisomes: reduction of mitochondrial reactive oxygen species (ROS) generation associated with fatty acid (FA) oxidation. This not only explains the mitochondrial involvement, but also its apparent absence in yeast. The latest results allow a reconstruction of the evolution of the yeast's highly derived metabolism and its limitations as a model organism in this instance. As I review here, peroxisomes are eukaryotic inventions reflecting mutual host endosymbiont adaptations: this is predicted by symbiogenetic theory, which states that the defining eukaryotic characteristics evolved as a result of mutual adaptations of two merging prokaryotes.See also the video abstract here: https://youtu.be/ HtyKhQ3DSxg

show abstract

The Blood Brain Barrier — Regulation of Fatty Acid and Drug Transport

Cited by 19 publications

References 151 publications

Reduction in cardiolipin decreases mitochondrial spare respiratory capacity and increases glucose transport into and across human brain cerebral microvascular endothelial cells

Reduction in cardiolipin decreases mitochondrial spare respiratory capacity and increases glucose transport into and across human brain cerebral microvascular endothelial cells

Generation of Bioactive Oxylipins from Exogenously Added Arachidonic, Eicosapentaenoic and Docosahexaenoic Acid in Primary Human Brain Microvessel Endothelial Cells

Evolution of peroxisomes illustrates symbiogenesis

Contact Info

Product

Resources

About