scholarly journals Amino acid transporters in the regulation of insulin secretion and signalling

2019 ◽  
Vol 47 (2) ◽  
pp. 571-590 ◽  
Author(s):  
Kiran Javed ◽  
Stephen J. Fairweather
Keyword(s):  
Amino Acids ◽  
Small Intestine ◽  
Insulin Secretion ◽  
Amino Acid ◽  
Insulin Signalling ◽  
Amino Acid Transporter ◽  
Fibroblast Growth Factor 21 ◽  
Amino Acid Transporters ◽  
Acid Transporter

Abstract Amino acids are increasingly recognised as modulators of nutrient disposal, including their role in regulating blood glucose through interactions with insulin signalling. More recently, cellular membrane transporters of amino acids have been shown to form a pivotal part of this regulation as they are primarily responsible for controlling cellular and circulating amino acid concentrations. The availability of amino acids regulated by transporters can amplify insulin secretion and modulate insulin signalling in various tissues. In addition, insulin itself can regulate the expression of numerous amino acid transporters. This review focuses on amino acid transporters linked to the regulation of insulin secretion and signalling with a focus on those of the small intestine, pancreatic β-islet cells and insulin-responsive tissues, liver and skeletal muscle. We summarise the role of the amino acid transporter B0AT1 (SLC6A19) and peptide transporter PEPT1 (SLC15A1) in the modulation of global insulin signalling via the liver-secreted hormone fibroblast growth factor 21 (FGF21). The role of vesicular vGLUT (SLC17) and mitochondrial SLC25 transporters in providing glutamate for the potentiation of insulin secretion is covered. We also survey the roles SNAT (SLC38) family and LAT1 (SLC7A5) amino acid transporters play in the regulation of and by insulin in numerous affective tissues. We hypothesise the small intestine amino acid transporter B0AT1 represents a crucial nexus between insulin, FGF21 and incretin hormone signalling pathways. The aim is to give an integrated overview of the important role amino acid transporters have been found to play in insulin-regulated nutrient signalling.

ACE2 and gut amino acid transport

2020 ◽  
Vol 134 (21) ◽  
pp. 2823-2833 ◽  
Author(s):  
Simone M.R. Camargo ◽  
Raphael N. Vuille-dit-Bille ◽  
Chantal F. Meier ◽  
François Verrey
Keyword(s):  
Amino Acids ◽  
Small Intestine ◽  
Amino Acid ◽  
Amino Acid Transporter ◽  
Neutral Amino Acid ◽  
Amino Acid Transporters ◽  
Type I ◽  
Small Intestinal Mucosa ◽  
Neutral Amino Acid Transporter ◽  
Acid Transporter

Abstract ACE2 is a type I membrane protein with extracellular carboxypeptidase activity displaying a broad tissue distribution with highest expression levels at the brush border membrane (BBM) of small intestine enterocytes and a lower expression in stomach and colon. In small intestinal mucosa, ACE2 mRNA expression appears to increase with age and to display higher levels in patients taking ACE-inhibitors (ACE-I). There, ACE2 protein heterodimerizes with the neutral amino acid transporter Broad neutral Amino acid Transporter 1 (B0AT1) (SLC6A19) or the imino acid transporter Sodium-dependent Imino Transporter 1 (SIT1) (SLC6A20), associations that are required for the surface expression of these transport proteins. These heterodimers can form quaternary structures able to function as binding sites for SARS-CoV-2 spike glycoproteins. The heterodimerization of the carboxypeptidase ACE2 with B0AT1 is suggested to favor the direct supply of substrate amino acids to the transporter, but whether this association impacts the ability of ACE2 to mediate viral infection is not known. B0AT1 mutations cause Hartnup disorder, a condition characterized by neutral aminoaciduria and, in some cases, pellagra-like symptoms, such as photosensitive rash, diarrhea, and cerebellar ataxia. Correspondingly, the lack of ACE2 and the concurrent absence of B0AT1 expression in small intestine causes a decrease in l-tryptophan absorption, niacin deficiency, decreased intestinal antimicrobial peptide production, and increased susceptibility to inflammatory bowel disease (IBD) in mice. Thus, the abundant expression of ACE2 in small intestine and its association with amino acid transporters appears to play a crucial role for the digestion of peptides and the absorption of amino acids and, thereby, for the maintenance of structural and functional gut integrity.

The Role of Large Neutral Amino Acid Transporter (LAT1) in Cancer

2019 ◽  
Vol 19 (11) ◽  
pp. 863-876 ◽  
Author(s):  
Xinjie Lu
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Metabolic Networks ◽  
Amino Acid Transporter ◽  
Amino Acid Transporters ◽  
Large Neutral Amino Acid ◽  
Pharmaceutical Drugs ◽  
Cationic Amino Acid ◽  
Acid Transporter

Background: The solute carrier family 7 (SLC7) can be categorically divided into two subfamilies, the L-type amino acid transporters (LATs) including SLC7A5-13, and SLC7A15, and the cationic amino acid transporters (CATs) including SLC7A1-4 and SLC7A14. Members of the CAT family transport predominantly cationic amino acids by facilitating diffusion with intracellular substrates. LAT1 (also known as SLC7A5), is defined as a heteromeric amino acid transporter (HAT) interacting with the glycoprotein CD98 (SLC3A2) through a conserved disulfide to uptake not only large neutral amino acids, but also several pharmaceutical drugs to cells. Methods: In this review, we provide an overview of the interaction of the structure-function of LAT1 and its essential role in cancer, specifically, its role at the blood-brain barrier (BBB) to facilitate the transport of thyroid hormones, pharmaceuticals (e.g., I-DOPA, gabapentin), and metabolites into the brain. Results: LAT1 expression increases as cancers progress, leading to higher expression levels in highgrade tumors and metastases. In addition, LAT1 plays a crucial role in cancer-associated reprogrammed metabolic networks by supplying tumor cells with essential amino acids. Conclusion: The increasing understanding of the role of LAT1 in cancer has led to an increase in interest surrounding its potential as a drug target for cancer treatment.

scholarly journals The L-Type Amino Acid Transporter LAT1—An Emerging Target in Cancer

2019 ◽  
Vol 20 (10) ◽  
pp. 2428 ◽  
Author(s):  
Pascal Häfliger ◽  
Roch-Philippe Charles
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Cancer Cells ◽  
Cell Mass ◽  
Essential Amino Acids ◽  
Amino Acid Transporter ◽  
Membrane Transporters ◽  
Preclinical Studies ◽  
Acid Transporter

Chronic proliferation is a major hallmark of tumor cells. Rapidly proliferating cancer cells are highly dependent on nutrients in order to duplicate their cell mass during each cell division. In particular, essential amino acids are indispensable for proliferating cancer cells. Their uptake across the cell membrane is tightly controlled by membrane transporters. Among those, the L-type amino acid transporter LAT1 (SLC7A5) has been repeatedly found overexpressed in a vast variety of cancers. In this review, we summarize the most recent advances in our understanding of the role of LAT1 in cancer and highlight preclinical studies and drug developments underlying the potential of LAT1 as therapeutic target.

scholarly journals The amino acid transporter CG1139 is required for retrograde transport and fast recovery of gut enterocytes after Serratia marcescens intestinal infection

2021 ◽  
Author(s):  
Catherine Socha ◽  
Ines S. Pais ◽  
Kwang-Zin Lee ◽  
Matthieu Lestradet ◽  
Dominique Ferrandon
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Serratia Marcescens ◽  
Retrograde Transport ◽  
Resistance Mechanisms ◽  
Amino Acid Transporter ◽  
Amino Acid Transporters ◽  
Intestinal Infections ◽  
Acid Transporter ◽  
Normal Thickness

The intestinal tract is constantly exposed to microbes. Severe infections can arise following the ingestion of pathogenic microbes from contaminating food or water sources. The host directly fights off ingested pathogens with resistance mechanisms, the immune response, or withstands and repairs the damages inflicted either by virulence factors or the host immune effectors, through tolerance/resilience mechanisms. In a previous study, we reported the existence in Drosophila melanogaster of a novel evolutionarily conserved resilience mechanism to intestinal infections with a hemolysin-positive Serratia marcescens strain (SmDb11), the purge of the apical cytoplasm of enterocytes. The epithelium becomes very thin and recovers rapidly, regaining its normal thickness within several hours. Here, we found that this recovery of gut enterocyte morphology is based on the host internal reserves and not on ingested food. Indeed, we observed a retrograde transport of amino acids from the host hemolymph to the enterocytes. We have identified several amino acid transporters required for recovery and we focused on the SLC36 family transporter CG1139. CG1139 is required for the retrograde transport of amino acids. RNA sequencing revealed that genes involved in the positive regulation of growth were observed in wild-type but not CG1139 mutant guts, in which the expression of Myc and genes involved in Insulin signaling is down-regulated. Functional analysis revealed that Myc is also required for the recovery of the thick gut epithelium after infection. Altogether, our results show the importance of an amino acid transporter in the fast regrowth of the enterocytes upon infection. Unexpectedly, we found that this transporter acts non cell-autonomously and can regulate the transcription of other genes, suggesting a signaling function of CG1139 that therefore appears to act as a transceptor.

scholarly journals The Regulation and Function of the L-Type Amino Acid Transporter 1 (LAT1) in Cancer

2018 ◽  
Vol 19 (8) ◽  
pp. 2373 ◽  
Author(s):  
Travis Salisbury ◽  
Subha Arthur
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Cancer Cells ◽  
Amino Acid Uptake ◽  
Essential Amino Acids ◽  
Amino Acid Transporter ◽  
Amino Acid Transporters ◽  
Acid Uptake ◽  
Cancer Pathways ◽  
Acid Transporter

The progression of cancer is associated with increases in amino acid uptake by cancer cells. Upon their entry into cells through specific transporters, exogenous amino acids are used to synthesize proteins, nucleic acids and lipids and to generate ATP. The essential amino acid leucine is also important for maintaining cancer-associated signaling pathways. By upregulating amino acid transporters, cancer cells gain greater access to exogenous amino acids to support chronic proliferation, maintain metabolic pathways, and to enhance certain signal transduction pathways. Suppressing cancer growth by targeting amino acid transporters will require an in-depth understanding of how cancer cells acquire amino acids, in particular, the transporters involved and which cancer pathways are most sensitive to amino acid deprivation. L-Type Amino Acid Transporter 1 (LAT1) mediates the uptake of essential amino acids and its expression is upregulated during the progression of several cancers. We will review the upstream regulators of LAT1 and the downstream effects caused by the overexpression of LAT1 in cancer cells.

scholarly journals Cloning, Expression, and Functional Characterization of Secondary Amino Acid Transporters of Lactococcus lactis

2012 ◽  
Vol 195 (2) ◽  
pp. 340-350 ◽  
Author(s):  
Hein Trip ◽  
Niels L. Mulder ◽  
Juke S. Lolkema
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Lactococcus Lactis ◽  
Aromatic Amino Acids ◽  
Amino Acid Transporter ◽  
Amino Acid Transporters ◽  
Acid Uptake ◽  
Content Type ◽  
Secondary Amino ◽  
Acid Transporter

ABSTRACTFourteen genes encoding putative secondary amino acid transporters were identified in the genomes ofLactococcus lactissubsp.cremorisstrains MG1363 and SK11 andL. lactissubsp. lactisstrains IL1403 and KF147, 12 of which were common to all four strains. Amino acid uptake inL. lactiscells overexpressing the genes revealed transporters specific for histidine, lysine, arginine, agmatine, putrescine, aromatic amino acids, acidic amino acids, serine, and branched-chain amino acids. Substrate specificities were demonstrated by inhibition profiles determined in the presence of excesses of the other amino acids. Four knockout mutants, lacking the lysine transporter LysP, the histidine transporter HisP (formerly LysQ), the acidic amino acid transporter AcaP (YlcA), or the aromatic amino acid transporter FywP (YsjA), were constructed. The LysP, HisP, and FywP deletion mutants showed drastically decreased rates of uptake of the corresponding substrates at low concentrations. The same was observed for the AcaP mutant with aspartate but not with glutamate. In rich M17 medium, the deletion of none of the transporters affected growth. In contrast, the deletion of the HisP, AcaP, and FywP transporters did affect growth in a defined medium with free amino acids as the sole amino acid source. HisP was essential at low histidine concentrations, and AcaP was essential in the absence of glutamine. FywP appeared to play a role in retaining intracellularly synthesized aromatic amino acids when these were not added to the medium. Finally, HisP, AcaP, and FywP did not play a role in the excretion of accumulated histidine, glutamate, or phenylalanine, respectively, indicating the involvement of other transporters.

scholarly journals Intestinal IMINO transporter SIT1 is not expressed in human newborns

2018 ◽  
Vol 315 (5) ◽  
pp. G887-G895 ◽  
Author(s):  
C. Meier ◽  
S. M. Camargo ◽  
S. Hunziker ◽  
U. Moehrlen ◽  
S. J. Gros ◽  
...  
Keyword(s):  
Small Intestine ◽  
Amino Acid ◽  
Amniotic Fluid ◽  
Amino Acid Transporter ◽  
Amino Acid Transporters ◽  
Accessory Proteins ◽  
Mrna Levels ◽  
Small Intestinal ◽  
Acid Transporter ◽  
Transporter Expression

The expression of amino acid transporters in small intestine epithelia of human newborns has not been studied yet. It is further not known whether the maturation of imino acid (proline) transport is delayed as in the kidney proximal tubule. The possibility to obtain small intestinal tissue from patients undergoing surgery for jejunal or ileal atresia during their first days after birth was used to address these questions. As control, adult terminal ileum tissue was sampled during routine endoscopies. Gene expression of luminal imino and amino acid transporter SIT1 (SLC6A20) was approximately threefold lower in newborns versus adults. mRNA levels of all other luminal and basolateral amino acid transporters and accessory proteins tested were similar in newborn mucosa compared with adults. At the protein level, the major luminal neutral amino acid transporter B0AT1 (SLC6A19) and its accessory protein angiotensin-converting enzyme 2 were shown by immunofluorescence to be expressed similarly in newborns and in adults. SIT1 protein was not detectable in the small intestine of human newborns, in contrast to adults. The morphology of newborn intestinal mucosa proximal and distal to the obstruction was generally normal, but a decreased proliferation rate was visualized distally of the atresia by lower levels of the mitosis marker Ki-67. The mRNA level of the 13 tested amino acid transporters and accessory proteins was nonetheless similar, suggesting that the intestinal obstruction and interruption of amniotic fluid passage through the small intestinal lumen did not affect amino acid transporter expression. NEW & NOTEWORTHY System IMINO transporter SIT1 is not expressed in the small intestine of human newborns. This new finding resembles the situation in the proximal kidney tubule leading to iminoglycinuria. Lack of amniotic fluid passage in small intestinal atresia does not affect amino acid transporter expression distal to intestinal occlusion.

scholarly journals Pichia pastoris and the Recombinant Human Heterodimeric Amino Acid Transporter 4F2hc-LAT1: From Clone Selection to Pure Protein

2021 ◽  
Vol 4 (3) ◽  
pp. 51
Author(s):  
Satish Kantipudi ◽  
Daniel Harder ◽  
Sara Bonetti ◽  
Dimitrios Fotiadis ◽  
Jean-Marc Jeckelmann
Keyword(s):  
Amino Acid ◽  
Pichia Pastoris ◽  
Protein Complexes ◽  
Amino Acid Transporter ◽  
Amino Acid Transporters ◽  
Expression Host ◽  
Amino Acids And Derivatives ◽  
Heterodimeric Complex ◽  
Acid Transporter ◽  
And Function

Heterodimeric amino acid transporters (HATs) are protein complexes composed of two subunits, a heavy and a light subunit belonging to the solute carrier (SLC) families SLC3 and SLC7. HATs transport amino acids and derivatives thereof across the plasma membrane. The human HAT 4F2hc-LAT1 is composed of the type-II membrane N-glycoprotein 4F2hc (SLC3A2) and the L-type amino acid transporter LAT1 (SLC7A5). 4F2hc-LAT1 is medically relevant, and its dysfunction and overexpression are associated with autism and tumor progression. Here, we provide a general applicable protocol on how to screen for the best membrane transport protein-expressing clone in terms of protein amount and function using Pichia pastoris as expression host. Furthermore, we describe an overexpression and purification procedure for the production of the HAT 4F2hc-LAT1. The isolated heterodimeric complex is pure, correctly assembled, stable, binds the substrate L-leucine, and is thus properly folded. Therefore, this Pichia pastoris-derived recombinant human 4F2hc-LAT1 sample can be used for downstream biochemical and biophysical characterizations.

scholarly journals Amino Acid Transporter LAT1 (SLC7A5) Mediates MeHg-Induced Oxidative Stress Defense in the Human Placental Cell Line HTR-8/SVneo

2021 ◽  
Vol 22 (4) ◽  
pp. 1707
Author(s):  
Sebastian Granitzer ◽  
Raimund Widhalm ◽  
Martin Forsthuber ◽  
Isabella Ellinger ◽  
Gernot Desoye ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Amino Acid ◽  
De Novo ◽  
Structural Similarity ◽  
Amino Acid Transporter ◽  
Cell Number ◽  
Mehg Exposure ◽  
Acid Transporter ◽  
And Oxidative Stress

The placental barrier can protect the fetus from contact with harmful substances. The potent neurotoxin methylmercury (MeHg), however, is very efficiently transported across the placenta. Our previous data suggested that L-type amino acid transporter (LAT)1 is involved in placental MeHg uptake, accepting MeHg-L-cysteine conjugates as substrate due to structural similarity to methionine. The aim of the present study was to investigate the antioxidant defense of placental cells to MeHg exposure and the role of LAT1 in this response. When trophoblast-derived HTR-8/SVneo cells were LAT1 depleted by siRNA-mediated knockdown, they accumulated less MeHg. However, they were more susceptible to MeHg-induced toxicity. This was evidenced in decreased cell viability at a usually noncytotoxic concentration of 0.03 µM MeHg (~6 µg/L). Treatment with ≥0.3 µM MeHg increased cytotoxicity, apoptosis rate, and oxidative stress of HTR-8/SVneo cells. These effects were enhanced under LAT1 knockdown. Reduced cell number was seen when MeHg-exposed cells were cultured in medium low in cysteine, a constituent of the tripeptide glutathione (GSH). Because LAT1-deficient HTR-8/SVneo cells have lower GSH levels than control cells (independent of MeHg treatment), we conclude that LAT1 is essential for de novo synthesis of GSH, required to counteract oxidative stress. Genetic predisposition to decreased LAT1 function combined with MeHg exposure could increase the risk of placental damage.

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