Insights into major facilitator superfamily domain‐containing protein‐2a (Mfsd2a) in physiology and pathophysiology. What do we know so far?

Ocak, Pınar Eser; Ocak, Umut; Sherchan, Prativa; Zhang, Junyi; Tang, Jiping

doi:10.1002/jnr.24327

Cited by 34 publications

(23 citation statements)

References 117 publications

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“…In terms of the chronic phase post-injury, there is a lack of evidence regarding the response of cerebrovascular Mfsd2a to head trauma. That said, while Mfsd2a levels are generally decreased in acute conditions such as intracerebral hemorrhage, Mfsd2a has been shown to be largely upregulated in more chronic disorders such as chronic liver injury and in ammatory bowel disease (Eser Ocak, Ocak, Sherchan, Zhang, et al, 2020). In line with these studies, we observed a progressive increase in cerebrovascular Mfsd2a levels in the chronic phase post-injury (6 months following r-mTBI).…”

Section: Discussionsupporting

confidence: 87%

Influence of Traumatic Brain Injury on Extracellular Tau Elimination at the Blood-Brain Barrier

Eisenbaum

Pearson

Gratkowski

et al. 2021

Preprint

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Repetitive head trauma has been associated with the accumulation of tau species in the brain. Our prior work showed brain vascular mural cells contribute to tau processing in the brain, and that these cells progressively degenerate following repetitive mild traumatic brain injury (r-mTBI). The current studies investigated the role of the cerebrovasculature in the elimination of extracellular tau from the brain, and the influence of r-mTBI on these processes. Following intracranial injection, the levels of exogenous tau residing in the brain were elevated in a mouse model of r-mTBI at 12 months post-injury compared to r-sham mice, indicating reduced tau elimination from the brain following head trauma. This may be the result of decreased caveolin-1 mediated tau efflux at the blood-brain barrier (BBB), as the caveolin inhibitor, methyl-β-cyclodextrin, significantly reduced tau uptake in isolated cerebrovessels and significantly decreased the basolateral-to-apical transit of tau across an in vitro model of the BBB. Moreover, we found that the upstream regulator of endothelial caveolin-1, Mfsd2a, was elevated in r-mTBI cerebrovessels compared to r-sham, which coincided with a decreased expression of cerebrovascular caveolin-1 at 6 months post-injury. Lastly, angiopoietin-1, a mural cell-derived protein governing endothelial Mfsd2a expression, was secreted to a greater extent from r-mTBI cerebrovessels compared to r-sham animals. Thus, in the chronic phase post-injury, release of angiopoietin-1 from degenerating mural cells downregulates caveolin-1 expression in brain endothelia, resulting in decreased tau elimination across the BBB, which may describe the accumulation of tau species in the brain following head trauma.

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Section: Discussionsupporting

confidence: 87%

Influence of Traumatic Brain Injury on Extracellular Tau Elimination at the Blood-Brain Barrier

Eisenbaum

Pearson

Gratkowski

et al. 2021

Preprint

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“…The blood-brain barrier (BBB) is a specialized multicellular membrane of astrocytes, pericytes, and endothelial cells that control the selective uptake of molecules into the brain and keep away toxins and pathogens. BBB provides an optimal environment for brain function [15]. Recently, a transmembrane protein named Major Facilitator Superfamily Domain containing 2A (MFSD2a) was described as the primary carrier for the DHA uptake, and other long-chain FA such as lyso-phospholipids (Lyso-PL) in BBB [16] and in retinal pigment epithelium [17].…”

Section: Introductionmentioning

confidence: 99%

Decreased Blood Level of MFSD2a as a Potential Biomarker of Alzheimer’s Disease

Sánchez-Campillo

Ruiz-Pastor

Gázquez

et al. 2019

IJMS

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The protein Major Facilitator Superfamily Domain containing 2A (MFSD2a) was recently described as the primary carrier for docosahexaenoic acid (DHA) into the brain. Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by lower DHA levels in blood lipids. The aim of this study was to investigate the expression of MFSD2a in the whole blood and brain as a potential biomarker of AD. Three groups were established: 38 healthy controls, 48 subjects with moderate AD (GDS4), and 47 with severe AD (GDS6). We analyzed postmortem brain samples from the hippocampus of 11 healthy controls and 11 severe AD patients. Fatty acid (FA) was determined in serum and brain by gas chromatography. Blood and brain MFSD2a protein expression was analyzed by Western blotting. We found a significant and progressive decline of MFSD2a levels in blood of AD patients (Control 0.83 ± 0.13, GDS4 0.72 ± 0.09, GDS6 0.48 ± 0.05*, p ˂ 0.01). We also corroborated a significant reduction of DHA and other n-3 long-chain polyunsaturated FA in serum of AD. No differences were found in MFSD2a expression or FA levels in brain of controls and AD subjects. MFSD2A carrier was analyzed in AD patients for the first time and the level of MFSD2a in the whole blood could be a potential biomarker of this disease.

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“…An example of a gene with a shared response to high fat diet is MFSD2A (Fig. 4e,f), which is a known regulator of metabolism in the liver [44,45]. This gene is proximal to a shared responsive regulatory element (Fig.…”

Section: Resultsmentioning

confidence: 99%

Regulatory diversity contributes to a divergent transcriptional response to dietary changes in mammals

Costello¹,

Shin²,

Trac³

et al. 2020

Preprint

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BACKGROUND: Regulatory innovation is central to the evolution of species. Different nutritional sources are one environmental pressure that can lead to selection for novel regulatory elements. Dietary composition changes, including exposure to "western" diets with excess fat and sugar content, can lead to transcriptional regulatory changes in the liver. In order to investigate how transcriptional regulatory changes in response to a high fat diet diverge across species, we profiled chromatin accessibility, histone modifications and the transcriptome in livers of rhesus macaques and mice fed high fat and normal diets. RESULTS: While the majority of elements exhibiting changes in chromatin accessibility in response to a high fat diet are enriched for similar transcription factors across species, the loci that change are mostly species specific. These unique responsive regulatory elements are largely derived from transposable elements and are enriched for liver-specific transcription factors, such as HNF4ɑ. Furthermore, the majority of genes that respond to a high fat diet in rhesus macaques do not have a shared response in mice and are proximal to regulatory elements that display changes in chromatin accessibility only in rhesus macaques. CONCLUSIONS: Our study demonstrates that most of the liver regulatory elements that exhibit changes in chromatin accessibility in response to a high fat diet do so in a species-specific manner. These findings illustrate how a similar environmental stimulus can drive a divergent chromatin and transcriptional responses in evolutionary distinct mammalian species.

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Insights into major facilitator superfamily domain‐containing protein‐2a (Mfsd2a) in physiology and pathophysiology. What do we know so far?

Cited by 34 publications

References 117 publications

Influence of Traumatic Brain Injury on Extracellular Tau Elimination at the Blood-Brain Barrier

Influence of Traumatic Brain Injury on Extracellular Tau Elimination at the Blood-Brain Barrier

Decreased Blood Level of MFSD2a as a Potential Biomarker of Alzheimer’s Disease

Regulatory diversity contributes to a divergent transcriptional response to dietary changes in mammals

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