Solute Carrier Transporters as Potential Targets for the Treatment of Metabolic Disease

Schumann, Tina; König, Jörg; Henke, Christine; Willmes, Diana M.; Bornstein, Stefan R.; Jordan, Jens; Fromm, Martin F.; Birkenfeld, Andreas L.

doi:10.1124/pr.118.015735

Cited by 105 publications

(70 citation statements)

References 380 publications

(539 reference statements)

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“…Over the past few decades, the advent of genomic sequencing coupled with genome-wide association studies has rapidly expanded our knowledge of the number of membrane transport proteins underpinning the pathophysiology of various human diseases ranging from cancer to metabolic diseases such as obesity, type 2 diabetes and osteoporosis (reviewed extensively in Lin et al (2015a), Zhang Y. et al (2018), Schumann et al (2020). Not surprisingly, unraveling the substrates transported and molecular mechanisms regulating transporter activity has been the focus of intense scientific and pharmaceutical inquiry in recent years, in pursuit of lucrative therapeutic targets against these critical yet largely untapped protein superfamilies (ésar-Razquin et al, 2015).…”

Section: Therapeutic Potential Of Membrane Transport Proteins For Metmentioning

confidence: 99%

Membrane Transport Proteins in Osteoclasts: The Ins and Outs

Ribet

Pavlos

2021

Front. Cell Dev. Biol.

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During bone resorption, the osteoclast must sustain an extraordinarily low pH environment, withstand immense ionic pressures, and coordinate nutrient and waste exchange across its membrane to sustain its unique structural and functional polarity. To achieve this, osteoclasts are equipped with an elaborate set of membrane transport proteins (pumps, transporters and channels) that serve as molecular ‘gatekeepers’ to regulate the bilateral exchange of ions, amino acids, metabolites and macromolecules across the ruffled border and basolateral domains. Whereas the importance of the vacuolar-ATPase proton pump and chloride voltage-gated channel 7 in osteoclasts has long been established, comparatively little is known about the contributions of other membrane transport proteins, including those categorized as secondary active transporters. In this Special Issue review, we provide a contemporary update on the ‘ins and outs’ of membrane transport proteins implicated in osteoclast differentiation, function and bone homeostasis and discuss their therapeutic potential for the treatment of metabolic bone diseases.

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Section: Therapeutic Potential Of Membrane Transport Proteins For Metmentioning

confidence: 99%

Membrane Transport Proteins in Osteoclasts: The Ins and Outs

Ribet

Pavlos

2021

Front. Cell Dev. Biol.

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“…Furthermore, UCP2 is required in the aspartate–argininosuccinate shunt of the tricarboxylic acid/urea cycle, since this carrier can exchange the cytosolic malate synthesized by cytosolic fumarase from fumarate [ 98 ], for intramitochondrial aspartate, which is then utilized in the cytosolic reactions of the urea cycle [ 99 ]. The activation of UCP2 can negatively modulate insulin secretion, impairing beta-cell functions [ 97 , 100 , 101 , 102 ]. On the other hand, mutations found in hUCP2 are responsible for human congenital hyperinsulinism [ 103 , 104 ].…”

Section: Drosophila Melanogaster Vs Human Mitomentioning

confidence: 99%

Drosophila melanogaster Mitochondrial Carriers: Similarities and Differences with the Human Carriers

Curcio

Lunetti

Zara

et al. 2020

IJMS

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Mitochondrial carriers are a family of structurally related proteins responsible for the exchange of metabolites, cofactors and nucleotides between the cytoplasm and mitochondrial matrix. The in silico analysis of the Drosophila melanogaster genome has highlighted the presence of 48 genes encoding putative mitochondrial carriers, but only 20 have been functionally characterized. Despite most Drosophila mitochondrial carrier genes having human homologs and sharing with them 50% or higher sequence identity, D. melanogaster genes display peculiar differences from their human counterparts: (1) in the fruit fly, many genes encode more transcript isoforms or are duplicated, resulting in the presence of numerous subfamilies in the genome; (2) the expression of the energy-producing genes in D. melanogaster is coordinated from a motif known as Nuclear Respiratory Gene (NRG), a palindromic 8-bp sequence; (3) fruit-fly duplicated genes encoding mitochondrial carriers show a testis-biased expression pattern, probably in order to keep a duplicate copy in the genome. Here, we review the main features, biological activities and role in the metabolism of the D. melanogaster mitochondrial carriers characterized to date, highlighting similarities and differences with their human counterparts. Such knowledge is very important for obtaining an integrated view of mitochondrial function in D. melanogaster metabolism.

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“…nutrients, metabolites) across the plasma membrane and membranes of subcellular organelles (e.g. mitochondria, lysosomes) [ 1 , 2 ]. Although expressed throughout the body, transport proteins are particularly expressed at higher density and in a broader spectrum in the liver, intestine, kidney, and placenta where several nutrients and metabolites are secreted or absorbed/reabsorbed [ 1 , 2 ].…”

Section: Introductionmentioning

confidence: 99%

“…mitochondria, lysosomes) [ 1 , 2 ]. Although expressed throughout the body, transport proteins are particularly expressed at higher density and in a broader spectrum in the liver, intestine, kidney, and placenta where several nutrients and metabolites are secreted or absorbed/reabsorbed [ 1 , 2 ]. Transporters are divided into two major groups: ATP-binding cassette (ABC) proteins and the solute carrier (SLC) proteins [ 1 ].…”

Section: Introductionmentioning

confidence: 99%

Consequences of NaCT/SLC13A5/mINDY deficiency: good versus evil, separated only by the blood–brain barrier

Kopel

Bhutia

Sivaprakasam

et al. 2021

Biochemical Journal

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NaCT/SLC13A5 is a Na+-coupled transporter for citrate in hepatocytes, neurons, and testes. It is also called mINDY (mammalian ortholog of ‘I'm Not Dead Yet’ in Drosophila). Deletion of Slc13a5 in mice leads to an advantageous phenotype, protecting against diet-induced obesity, and diabetes. In contrast, loss-of-function mutations in SLC13A5 in humans cause a severe disease, EIEE25/DEE25 (early infantile epileptic encephalopathy-25/developmental epileptic encephalopathy-25). The difference between mice and humans in the consequences of the transporter deficiency is intriguing but probably explainable by the species-specific differences in the functional features of the transporter. Mouse Slc13a5 is a low-capacity transporter, whereas human SLC13A5 is a high-capacity transporter, thus leading to quantitative differences in citrate entry into cells via the transporter. These findings raise doubts as to the utility of mouse models to evaluate NaCT biology in humans. NaCT-mediated citrate entry in the liver impacts fatty acid and cholesterol synthesis, fatty acid oxidation, glycolysis, and gluconeogenesis; in neurons, this process is essential for the synthesis of the neurotransmitters glutamate, GABA, and acetylcholine. Thus, SLC13A5 deficiency protects against obesity and diabetes based on what the transporter does in hepatocytes, but leads to severe brain deficits based on what the transporter does in neurons. These beneficial versus detrimental effects of SLC13A5 deficiency are separable only by the blood-brain barrier. Can we harness the beneficial effects of SLC13A5 deficiency without the detrimental effects? In theory, this should be feasible with selective inhibitors of NaCT, which work only in the liver and do not get across the blood-brain barrier.

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Solute Carrier Transporters as Potential Targets for the Treatment of Metabolic Disease

Cited by 105 publications

References 380 publications

Membrane Transport Proteins in Osteoclasts: The Ins and Outs

Membrane Transport Proteins in Osteoclasts: The Ins and Outs

Drosophila melanogaster Mitochondrial Carriers: Similarities and Differences with the Human Carriers

Consequences of NaCT/SLC13A5/mINDY deficiency: good versus evil, separated only by the blood–brain barrier

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