International Journal of Molecular Sciences

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Open AccessEditorial

Overcoming Biological Barriers: Importance of Membrane Transporters in Homeostasis, Disease and Disease Treatment

by Giuliano Ciarimboli

Int. J. Mol. Sci. 2023, 24(8), 7212; https://doi.org/10.3390/ijms24087212 - 13 Apr 2023

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Abstract

This editorial summarizes the 22 scientific papers published in the Special Issue “Overcoming Biological Barriers: Importance of Membrane Transporters in Homeostasis, Disease, and Disease Treatment” of the International Journal of Molecular Sciences [...] Full article

(This article belongs to the Special Issue Overcoming Biological Barriers: Importance of Membrane Transporters in Homeostasis, Disease, and Disease Treatment)

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15 pages, 790 KiB

Open AccessArticle

A Unique In Vitro Assay to Investigate ABCB4 Transport Function

by Csilla Temesszentandrási-Ambrus, Gábor Nagy, Annamária Bui and Zsuzsanna Gáborik

Int. J. Mol. Sci. 2023, 24(5), 4459; https://doi.org/10.3390/ijms24054459 - 24 Feb 2023

Cited by 4 | Viewed by 1806

Abstract

ABCB4 is almost exclusively expressed in the liver, where it plays an essential role in bile formation by transporting phospholipids into the bile. ABCB4 polymorphisms and deficiencies in humans are associated with a wide spectrum of hepatobiliary disorders, attesting to its crucial physiological [...] Read more.

ABCB4 is almost exclusively expressed in the liver, where it plays an essential role in bile formation by transporting phospholipids into the bile. ABCB4 polymorphisms and deficiencies in humans are associated with a wide spectrum of hepatobiliary disorders, attesting to its crucial physiological function. Inhibition of ABCB4 by drugs may lead to cholestasis and drug-induced liver injury (DILI), although compared with other drug transporters, there are only a few identified substrates and inhibitors of ABCB4. Since ABCB4 shares up to 76% identity and 86% similarity in the amino acid sequence with ABCB1, also known to have common drug substrates and inhibitors, we aimed to develop an ABCB4 expressing Abcb1-knockout MDCKII cell line for transcellular transport assays. This in vitro system allows the screening of ABCB4-specific drug substrates and inhibitors independently of ABCB1 activity. Abcb1KO-MDCKII-ABCB4 cells constitute a reproducible, conclusive, and easy to use assay to study drug interactions with digoxin as a substrate. Screening a set of drugs with different DILI outcomes proved that this assay is applicable to test ABCB4 inhibitory potency. Our results are consistent with prior findings concerning hepatotoxicity causality and provide new insights for identifying drugs as potential ABCB4 inhibitors and substrates. Full article

(This article belongs to the Special Issue Overcoming Biological Barriers: Importance of Membrane Transporters in Homeostasis, Disease, and Disease Treatment)

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33 pages, 4518 KiB

Open AccessArticle

Cloning and Characterization of Trypanosoma congolense and T. vivax Nucleoside Transporters Reveal the Potential of P1-Type Carriers for the Discovery of Broad-Spectrum Nucleoside-Based Therapeutics against Animal African Trypanosomiasis

by Marzuq A. Ungogo, Mustafa M. Aldfer, Manal J. Natto, Hainan Zhuang, Robyn Chisholm, Katy Walsh, MarieClaire McGee, Kayhan Ilbeigi, Jamal Ibrahim Asseri, Richard J. S. Burchmore, Guy Caljon, Serge Van Calenbergh and Harry P. De Koning

Int. J. Mol. Sci. 2023, 24(4), 3144; https://doi.org/10.3390/ijms24043144 - 05 Feb 2023

Cited by 6 | Viewed by 2036

Abstract

African Animal Trypanosomiasis (AAT), caused predominantly by Trypanosoma brucei brucei, T. vivax and T. congolense, is a fatal livestock disease throughout Sub-Saharan Africa. Treatment options are very limited and threatened by resistance. Tubercidin (7-deazaadenosine) analogs have shown activity against individual parasites [...] Read more.

African Animal Trypanosomiasis (AAT), caused predominantly by Trypanosoma brucei brucei, T. vivax and T. congolense, is a fatal livestock disease throughout Sub-Saharan Africa. Treatment options are very limited and threatened by resistance. Tubercidin (7-deazaadenosine) analogs have shown activity against individual parasites but viable chemotherapy must be active against all three species. Divergence in sensitivity to nucleoside antimetabolites could be caused by differences in nucleoside transporters. Having previously characterized the T. brucei nucleoside carriers, we here report the functional expression and characterization of the main adenosine transporters of T. vivax (TvxNT3) and T. congolense (TcoAT1/NT10), in a Leishmania mexicana cell line (‘SUPKO’) lacking adenosine uptake. Both carriers were similar to the T. brucei P1-type transporters and bind adenosine mostly through interactions with N3, N7 and 3′-OH. Expression of TvxNT3 and TcoAT1 sensitized SUPKO cells to various 7-substituted tubercidins and other nucleoside analogs although tubercidin itself is a poor substrate for P1-type transporters. Individual nucleoside EC₅₀s were similar for T. b. brucei, T. congolense, T. evansi and T. equiperdum but correlated less well with T. vivax. However, multiple nucleosides including 7-halogentubercidines displayed pEC50>7 for all species and, based on transporter and anti-parasite SAR analyses, we conclude that nucleoside chemotherapy for AAT is viable. Full article

(This article belongs to the Special Issue Overcoming Biological Barriers: Importance of Membrane Transporters in Homeostasis, Disease, and Disease Treatment)

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14 pages, 2279 KiB

Open AccessArticle

Investigations with Drugs and Pesticides Revealed New Species- and Substrate-Dependent Inhibition by Elacridar and Imazalil in Human and Mouse Organic Cation Transporter OCT2

by Annett Kuehne, Saskia Floerl and Yohannes Hagos

Int. J. Mol. Sci. 2022, 23(24), 15795; https://doi.org/10.3390/ijms232415795 - 13 Dec 2022

Cited by 2 | Viewed by 1416

Abstract

Multiple drugs are used to treat various indications as well as pesticides that are ingested unintentionally and enter the bloodstream. The residence time or bioavailability of these substances in circulation depends on several mechanisms, such as drug–drug interaction (DDI), drug–pesticide interaction, metabolizing enzymes [...] Read more.

Multiple drugs are used to treat various indications as well as pesticides that are ingested unintentionally and enter the bloodstream. The residence time or bioavailability of these substances in circulation depends on several mechanisms, such as drug–drug interaction (DDI), drug–pesticide interaction, metabolizing enzymes and the hepatic and renal transport systems, involved in the elimination of the compounds from the body. One of these transporters is the Organic Cation Transporter 2 (OCT2) member of the solute carrier (SLC22) transporter family. OCT2 is highly expressed in the proximal tubule epithelial cells in human and mouse kidney, where it mediates the uptake of endogenous organic cations as well as numerous drugs and xenobiotics, and contributes to the first step of renal clearance. In this study, we examined OCT2 on two subjects: First, the transferability of data from mouse to human, since mice are initially examined in the development of new drugs to assess the renal excretion of organic cations. Second, to what extent the choice of substrate affects the properties of an inhibitor. For this purpose, the functional properties of hOCT2 and mOct2 were validated under the same experimental conditions with the known substrates metformin and 1-Methyl-4-phenylpyridinium iodide (MPP). While hOCT2 and mOct2 showed very low affinities for metformin with K_m values of 3.9 mM and 3.5 mM, the affinity of hOCT2 and mOct2 for MPP (62 and 40 µM) was 64- and 89-fold higher, respectively. For our positive control inhibitor decynium22, we determined the following IC₅₀ values for hOCT2 and mOct2: 2.2 and 2.6 µM for metformin uptake, and 16 and 6.9 µM for MPP uptake. A correlation analysis of the inhibitory effects of 13 drugs and 9 pesticides on hOCT2- and mOct2-mediated transport of metformin showed a correlation coefficient R² of 0.88, indicating good interspecies correlation. Nevertheless, the bioenhancer elacridar and the fungicide imazalil showed species-dependent inhibitory potentials. Concentration-dependent inhibition of hOCT2- and mOct2-mediated metformin uptake by elacridar showed IC₅₀ values of 20 µM and 1.9 µM and by imazalil 4.7 µM and 0.58 µM, respectively. In conclusion, although our data show comparable species-independent interactions for most compounds, there can be large species–specific differences in the interactions of individual compounds, which should be considered when extrapolating data from mice to humans. Furthermore, a comparison of the inhibitory potential of elacridar and imazalil on metformin uptake with that on MPP uptake reveals substrate-dependent differences in hOCT2 and mOct2 for both inhibitors. Therefore, it might be useful to test two different substrates in inhibition studies. Full article

(This article belongs to the Special Issue Overcoming Biological Barriers: Importance of Membrane Transporters in Homeostasis, Disease, and Disease Treatment)

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13 pages, 1509 KiB

Open AccessArticle

Interaction of Masitinib with Organic Cation Transporters

by Saliha Harrach, Jasmin Haag, Martin Steinbüchel, Rita Schröter, Ute Neugebauer, Jessica Bertrand and Giuliano Ciarimboli

Int. J. Mol. Sci. 2022, 23(22), 14189; https://doi.org/10.3390/ijms232214189 - 16 Nov 2022

Cited by 4 | Viewed by 1548

Abstract

Tyrosine kinase inhibitors (TKI) such as Masitinib were reported to be useful as therapeutic options in malignant disorders and nonmalignant diseases, like coronavirus disease 2019 (COVID-19). Most kinases must be translocated into targeted cells by the action of specific transport proteins, as they [...] Read more.

Tyrosine kinase inhibitors (TKI) such as Masitinib were reported to be useful as therapeutic options in malignant disorders and nonmalignant diseases, like coronavirus disease 2019 (COVID-19). Most kinases must be translocated into targeted cells by the action of specific transport proteins, as they are hydrophilic and not able to cross cell membranes freely. Accordingly, the efficacy of TKI in target cells is closely dependent on the expression of their transporters. Specifically, Masitinib is an organic cation and is expected to interact with organic cation transporters (OCT and Multidrug and Toxin Extrusion proteins—MATE-). The aim of this work was to characterize the interaction of Masitinib with different OCTs. Human embryonic kidney 293 cells stably transfected with murine or human OCT were used for the experiments. The interaction of Masitinib with OCTs was investigated using quenching experiments. The intracellular accumulation of this drug was quantified using high performance liquid chromatography. Our results identified interactions of Masitinib with almost all investigated mouse (m) and human (h) OCTs and hMATE1 and indicated OCT1 and hOCT2 to be especially potent Masitinib translocators across cell membranes. Interestingly, some important differences were observed for the interaction with murine and human OCTs. In the future, investigations concerning further in vitro and in vivo properties of Masitinib and its efficacy related to transporter-related uptake mechanisms under pathophysiological conditions should be performed. Clinical trials in humans and other animals with Masitinib have already shown promising results. However, further research is necessary to understand the disease specific transport mechanisms of Masitinib to contribute to a successful and responsible therapy employment. Full article

(This article belongs to the Special Issue Overcoming Biological Barriers: Importance of Membrane Transporters in Homeostasis, Disease, and Disease Treatment)

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23 pages, 6658 KiB

Open AccessArticle

In Vitro Characterization of Renal Drug Transporter Activity in Kidney Cancer

by Pedro Caetano-Pinto, Nathanil Justian, Maria Dib, Jana Fischer, Maryna Somova, Martin Burchardt and Ingmar Wolff

Int. J. Mol. Sci. 2022, 23(17), 10177; https://doi.org/10.3390/ijms231710177 - 05 Sep 2022

Cited by 4 | Viewed by 2672

Abstract

The activity of drug transporters is central to the secretory function of the kidneys and a defining feature of renal proximal tubule epithelial cells (RPTECs). The expression, regulation, and function of these membrane-bound proteins is well understood under normal renal physiological conditions. However, [...] Read more.

The activity of drug transporters is central to the secretory function of the kidneys and a defining feature of renal proximal tubule epithelial cells (RPTECs). The expression, regulation, and function of these membrane-bound proteins is well understood under normal renal physiological conditions. However, the impact of drug transporters on the pathophysiology of kidney cancer is still elusive. In the present study, we employed different renal cell carcinoma (RCC) cell lines and a prototypical non-malignant RPTEC cell line to characterize the activity, expression, and potential regulatory mechanisms of relevant renal drug transporters in RCC in vitro. An analysis of the uptake and efflux activity, the expression of drug transporters, and the evaluation of cisplatin cytotoxicity under the effects of methylation or epidermal growth factor receptor (EGFR) inhibition showed that the RCC cells retained substantial drug transport activity. In RCC cells, P-glycoprotein was localized in the nucleus and its pharmacological inhibition enhanced cisplatin toxicity in non-malignant RPTECs. On the other hand, methylation inhibition enhanced cisplatin toxicity by upregulating the organic cation uptake activity in RCC cells. Differential effects of methylation and EGFR were observed in transporter expression, showing regulatory heterogeneity in these cells. Interestingly, the non-malignant RPTEC cell line that was used lacked the machinery responsible for organic cation transport, which reiterates the functional losses that renal cells undergo in vitro. Full article

(This article belongs to the Special Issue Overcoming Biological Barriers: Importance of Membrane Transporters in Homeostasis, Disease, and Disease Treatment)

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19 pages, 2628 KiB

Open AccessArticle

MATE1 Deficiency Exacerbates Dofetilide-Induced Proarrhythmia

by Muhammad Erfan Uddin, Eric D. Eisenmann, Yang Li, Kevin M. Huang, Dominique A. Garrison, Zahra Talebi, Alice A. Gibson, Yan Jin, Mahesh Nepal, Ingrid M. Bonilla, Qiang Fu, Xinxin Sun, Alec Millar, Mikhail Tarasov, Christopher E. Jay, Xiaoming Cui, Heidi J. Einolf, Ryan M. Pelis, Sakima A. Smith, Przemysław B. Radwański, Douglas H. Sweet, Jörg König, Martin F. Fromm, Cynthia A. Carnes, Shuiying Hu and Alex Sparreboom Show full author list Hide full author list

Int. J. Mol. Sci. 2022, 23(15), 8607; https://doi.org/10.3390/ijms23158607 - 03 Aug 2022

Cited by 4 | Viewed by 3092

Abstract

Dofetilide is a rapid delayed rectifier potassium current inhibitor widely used to prevent the recurrence of atrial fibrillation and flutter. The clinical use of this drug is associated with increases in QTc interval, which predispose patients to ventricular cardiac arrhythmias. The mechanisms involved [...] Read more.

Dofetilide is a rapid delayed rectifier potassium current inhibitor widely used to prevent the recurrence of atrial fibrillation and flutter. The clinical use of this drug is associated with increases in QTc interval, which predispose patients to ventricular cardiac arrhythmias. The mechanisms involved in the disposition of dofetilide, including its movement in and out of cardiomyocytes, remain unknown. Using a xenobiotic transporter screen, we identified MATE1 (SLC47A1) as a transporter of dofetilide and found that genetic knockout or pharmacological inhibition of MATE1 in mice was associated with enhanced retention of dofetilide in cardiomyocytes and increased QTc prolongation. The urinary excretion of dofetilide was also dependent on the MATE1 genotype, and we found that this transport mechanism provides a mechanistic basis for previously recorded drug-drug interactions of dofetilide with various contraindicated drugs, including bictegravir, cimetidine, ketoconazole, and verapamil. The translational significance of these observations was examined with a physiologically-based pharmacokinetic model that adequately predicted the drug-drug interaction liabilities in humans. These findings support the thesis that MATE1 serves a conserved cardioprotective role by restricting excessive cellular accumulation and warrant caution against the concurrent administration of potent MATE1 inhibitors and cardiotoxic substrates with a narrow therapeutic window. Full article

(This article belongs to the Special Issue Overcoming Biological Barriers: Importance of Membrane Transporters in Homeostasis, Disease, and Disease Treatment)

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14 pages, 3757 KiB

Open AccessArticle

Free Cholesterol Affects the Function and Localization of Human Na⁺/Taurocholate Cotransporting Polypeptide (NTCP) and Organic Cation Transporter 1 (OCT1)

by Jessica Y. Idowu and Bruno Hagenbuch

Int. J. Mol. Sci. 2022, 23(15), 8457; https://doi.org/10.3390/ijms23158457 - 30 Jul 2022

Cited by 7 | Viewed by 1711

Abstract

Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are associated with obesity. They are accompanied by increased levels of free cholesterol in the liver. Most free cholesterol resides within the plasma membrane. We assessed the impact of adding or removing free cholesterol [...] Read more.

Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are associated with obesity. They are accompanied by increased levels of free cholesterol in the liver. Most free cholesterol resides within the plasma membrane. We assessed the impact of adding or removing free cholesterol on the function and localization of two hepatocellular uptake transporters: the Na⁺/taurocholate cotransporting polypeptide (NTCP) and the organic cation transporter 1 (OCT1). We used a cholesterol–MCD complex (cholesterol) to add cholesterol and methyl-β-cyclodextrin (MCD) to remove cholesterol. Our results demonstrate that adding cholesterol decreases NTCP capacity from 132 ± 20 to 69 ± 37 µL/mg/min and OCT1 capacity from 209 ± 66 to 125 ± 26 µL/mg/min. Removing cholesterol increased NTCP and OCT1 capacity to 224 ± 65 and 279 ± 20 µL/mg/min, respectively. In addition, adding cholesterol increased the localization of NTCP within lipid rafts, while adding or removing cholesterol increased OCT1 localization in lipid rafts. These results demonstrate that increased cholesterol levels can impair NTCP and OCT1 function, suggesting that the free cholesterol content of the liver can alter bile acid and drug uptake into the liver. This could explain the increased plasma bile acid levels in NAFLD and NASH patients and potentially lead to altered drug disposition. Full article

(This article belongs to the Special Issue Overcoming Biological Barriers: Importance of Membrane Transporters in Homeostasis, Disease, and Disease Treatment)

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20 pages, 3854 KiB

Open AccessArticle

Nucleoside Transport and Nucleobase Uptake Null Mutants in Leishmania mexicana for the Routine Expression and Characterization of Purine and Pyrimidine Transporters

by Mustafa M. Aldfer, Tahani A. AlSiari, Hamza A. A. Elati, Manal J. Natto, Ibrahim A. Alfayez, Gustavo D. Campagnaro, Bashiru Sani, Richard J. S. Burchmore, George Diallinas and Harry P. De Koning

Int. J. Mol. Sci. 2022, 23(15), 8139; https://doi.org/10.3390/ijms23158139 - 23 Jul 2022

Cited by 9 | Viewed by 2021

Abstract

The study of transporters is highly challenging, as they cannot be isolated or studied in suspension, requiring a cellular or vesicular system, and, when mediated by more than one carrier, difficult to interpret. Nucleoside analogues are important drug candidates, and all protozoan pathogens [...] Read more.

The study of transporters is highly challenging, as they cannot be isolated or studied in suspension, requiring a cellular or vesicular system, and, when mediated by more than one carrier, difficult to interpret. Nucleoside analogues are important drug candidates, and all protozoan pathogens express multiple equilibrative nucleoside transporter (ENT) genes. We have therefore developed a system for the routine expression of nucleoside transporters, using CRISPR/cas9 to delete both copies of all three nucleoside transporters from Leishmania mexicana (ΔNT1.1/1.2/2 (SUPKO)). SUPKO grew at the same rate as the parental strain and displayed no apparent deficiencies, owing to the cells’ ability to synthesize pyrimidines, and the expression of the LmexNT3 purine nucleobase transporter. Nucleoside transport was barely measurable in SUPKO, but reintroduction of L. mexicana NT1.1, NT1.2, and NT2 restored uptake. Thus, SUPKO provides an ideal null background for the expression and characterization of single ENT transporter genes in isolation. Similarly, an LmexNT3-KO strain provides a null background for transport of purine nucleobases and was used for the functional characterization of T. cruzi NB2, which was determined to be adenine-specific. A 5-fluorouracil-resistant strain (Lmex5FURes) displayed null transport for uracil and 5FU, and was used to express the Aspergillus nidulans uracil transporter FurD. Full article

(This article belongs to the Special Issue Overcoming Biological Barriers: Importance of Membrane Transporters in Homeostasis, Disease, and Disease Treatment)

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13 pages, 2566 KiB

Open AccessArticle

Evolution of the Membrane Transport Protein Domain

by Siarhei A. Dabravolski and Stanislav V. Isayenkov

Int. J. Mol. Sci. 2022, 23(15), 8094; https://doi.org/10.3390/ijms23158094 - 22 Jul 2022

Cited by 2 | Viewed by 1705

Abstract

Membrane transport proteins are widely present in all living organisms, however, their function, transported substrate, and mechanism of action are unknown. Here we use diverse bioinformatics tools to investigate the evolution of MTPs, analyse domain organisation and loop topology, and study the comparative [...] Read more.

Membrane transport proteins are widely present in all living organisms, however, their function, transported substrate, and mechanism of action are unknown. Here we use diverse bioinformatics tools to investigate the evolution of MTPs, analyse domain organisation and loop topology, and study the comparative alignment of modelled 3D structures. Our results suggest a high level of conservancy between MTPs from different taxa on both amino acids and structural levels, which imply some degree of functional similarities. The presence of loop/s of different lengths in various positions suggests tax-on-specific adaptation to transported substrates, intracellular localisation, accessibility for post-translation modifications, and interaction with other proteins. The comparison of modelled structures proposes close relations and a common origin for MTP and Na/H exchanger. Further, a high level of amino acid similarity and identity between archaeal and bacterial MTPs and Na/H exchangers imply conservancy of ion transporting function at least for archaeal and bacterial MTPs. Full article

(This article belongs to the Special Issue Overcoming Biological Barriers: Importance of Membrane Transporters in Homeostasis, Disease, and Disease Treatment)

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13 pages, 937 KiB

Open AccessArticle

Protein Abundance of Drug Transporters in Human Hepatitis C Livers

by Marek Droździk, Joanna Lapczuk-Romanska, Christoph Wenzel, Łukasz Skalski, Sylwia Szeląg-Pieniek, Mariola Post, Marta Syczewska, Mateusz Kurzawski and Stefan Oswald

Int. J. Mol. Sci. 2022, 23(14), 7947; https://doi.org/10.3390/ijms23147947 - 19 Jul 2022

Cited by 11 | Viewed by 1540

Abstract

Transmembrane drug transport in hepatocytes is one of the major determinants of drug pharmacokinetics. In the present study, ABC transporters (P-gp, MRP1, MRP2, MRP3, MRP4, BCRP, and BSEP) and SLC transporters (MCT1, NTCP, OAT2, OATP1B1, OATP1B3, OATP2B1, OCT1, and OCT3) were quantified for [...] Read more.

Transmembrane drug transport in hepatocytes is one of the major determinants of drug pharmacokinetics. In the present study, ABC transporters (P-gp, MRP1, MRP2, MRP3, MRP4, BCRP, and BSEP) and SLC transporters (MCT1, NTCP, OAT2, OATP1B1, OATP1B3, OATP2B1, OCT1, and OCT3) were quantified for protein abundance (LC-MS/MS) and mRNA levels (qRT-PCR) in hepatitis C virus (HCV)-infected liver samples from the Child–Pugh class A (n = 30), B (n = 21), and C (n = 7) patients. Protein levels of BSEP, MRP3, MCT1, OAT2, OATP1B3, and OCT3 were not significantly affected by HCV infection. P-gp, MRP1, BCRP, and OATP1B3 protein abundances were upregulated, whereas those of MRP2, MRP4, NTCP, OATP2B1, and OCT1 were downregulated in all HCV samples. The observed changes started to be seen in the Child–Pugh class A livers, i.e., upregulation of P-gp and MRP1 and downregulation of MRP2, MRP4, BCRP, and OATP1B3. In the case of NTCP, OATP2B1, and OCT1, a decrease in the protein levels was observed in the class B livers. In the class C livers, no other changes were noted than those in the class A and B patients. The results of the study demonstrate that drug transporter protein abundances are affected by the functional state of the liver in hepatitis C patients. Full article

(This article belongs to the Special Issue Overcoming Biological Barriers: Importance of Membrane Transporters in Homeostasis, Disease, and Disease Treatment)

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13 pages, 1189 KiB

Open AccessArticle

Monocrotaline Toxicity Alters the Function of Hepatocyte Membrane Transporters in Rats

by Catherine M. Pastor and Valérie Vilgrain

Int. J. Mol. Sci. 2022, 23(14), 7928; https://doi.org/10.3390/ijms23147928 - 19 Jul 2022

Cited by 2 | Viewed by 1299

Abstract

Pyrrolizidine alkaloid monocrotaline (MCT) induces sinusoidal obstruction syndrome (SOS) in rats characterised by a sinusoidal congestive obstruction. Additionally, MCT administration decreases the biliary excretion of gadobenate dimeglumine (BOPTA), a hepatobiliary substrate used in clinical imaging. BOPTA crosses hepatocyte membranes through organic anion transporting [...] Read more.

Pyrrolizidine alkaloid monocrotaline (MCT) induces sinusoidal obstruction syndrome (SOS) in rats characterised by a sinusoidal congestive obstruction. Additionally, MCT administration decreases the biliary excretion of gadobenate dimeglumine (BOPTA), a hepatobiliary substrate used in clinical imaging. BOPTA crosses hepatocyte membranes through organic anion transporting polypeptides, multidrug-resistance-associated protein 2, and Mrp3/4 transporters, and a modified function of these transporters is likely to explain the decreased biliary excretion. This study compared BOPTA transport across hepatocytes in livers isolated from normal (Nl) rats and rats with intragastric administration of MCT. BOPTA hepatocyte influx clearance was similar in both groups, while biliary clearance and bile concentrations were much lower in MCT than in Nl livers. BOPTA efflux clearance back to the sinusoids compensated for the low biliary excretion, and hepatocyte concentrations remained similar in both groups. This SOS-associated changes of transporter functions might impact the pharmacokinetics of numerous drugs that use similar transporters to cross hepatocytes. Full article

(This article belongs to the Special Issue Overcoming Biological Barriers: Importance of Membrane Transporters in Homeostasis, Disease, and Disease Treatment)

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20 pages, 3458 KiB

Open AccessArticle

Bile Duct Ligation Impairs Function and Expression of Mrp1 at Rat Blood–Retinal Barrier via Bilirubin-Induced P38 MAPK Pathway Activations

by Ping Li, Yiting Yang, Zijin Lin, Shijin Hong, Ling Jiang, Han Zhou, Lu Yang, Liang Zhu, Xiaodong Liu and Li Liu

Int. J. Mol. Sci. 2022, 23(14), 7666; https://doi.org/10.3390/ijms23147666 - 11 Jul 2022

Cited by 5 | Viewed by 2188

Abstract

Liver injury is often associated with hepatic retinopathy, resulting from accumulation of retinal toxins due to blood–retinal barrier (BRB) dysfunction. Retinal pigment epithelium highly expresses MRP1/Mrp1. We aimed to investigate whether liver injury affects the function and expression of retinal Mrp1 using bile [...] Read more.

Liver injury is often associated with hepatic retinopathy, resulting from accumulation of retinal toxins due to blood–retinal barrier (BRB) dysfunction. Retinal pigment epithelium highly expresses MRP1/Mrp1. We aimed to investigate whether liver injury affects the function and expression of retinal Mrp1 using bile duct ligation (BDL) rats. Retinal distributions of fluorescein and 2,4-dinitrophenyl-S-glutathione were used for assessing Mrp1 function. BDL significantly increased distributions of the two substrates and bilirubin, downregulated Mrp1 protein, and upregulated phosphorylation of p38 and MK2 in the retina. BDL neither affected the retinal distribution of FITC-dextran nor expressions of ZO-1 and claudin-5, demonstrating intact BRB integrity. In ARPE-19 cells, BDL rat serum or bilirubin decreased MRP1 expression and enhanced p38 and MK2 phosphorylation. Both inhibiting and silencing p38 significantly reversed the bilirubin- and anisomycin-induced decreases in MRP1 protein. Apparent permeability coefficients of fluorescein in the A-to-B direction (P_{app, A-to-B}) across the ARPE-19 monolayer were greater than P_{app, B-to-A}. MK571 or bilirubin significantly decreased P_{app, A-to-B} of fluorescein. Bilirubin treatment significantly downregulated Mrp1 function and expression without affecting integrity of BRB and increased bilirubin levels and phosphorylation of p38 and MK2 in rat retina. In conclusion, BDL downregulates the expression and function of retina Mrp1 by activating the p38 MAPK pathway due to increased bilirubin levels. Full article

(This article belongs to the Special Issue Overcoming Biological Barriers: Importance of Membrane Transporters in Homeostasis, Disease, and Disease Treatment)

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30 pages, 4795 KiB

Open AccessArticle

Hepatic Expression of the Na⁺-Taurocholate Cotransporting Polypeptide Is Independent from Genetic Variation

by Roman Tremmel, Anne T. Nies, Barbara A. C. van Eijck, Niklas Handin, Mathias Haag, Stefan Winter, Florian A. Büttner, Charlotte Kölz, Franziska Klein, Pascale Mazzola, Ute Hofmann, Kathrin Klein, Per Hoffmann, Markus M. Nöthen, Fabienne Z. Gaugaz, Per Artursson, Matthias Schwab and Elke Schaeffeler

Int. J. Mol. Sci. 2022, 23(13), 7468; https://doi.org/10.3390/ijms23137468 - 05 Jul 2022

Cited by 5 | Viewed by 3415

Abstract

The hepatic Na⁺-taurocholate cotransporting polypeptide NTCP/SLC10A1 is important for the uptake of bile salts and selected drugs. Its inhibition results in increased systemic bile salt concentrations. NTCP is also the entry receptor for the hepatitis B/D virus. We investigated interindividual [...] Read more.

The hepatic Na⁺-taurocholate cotransporting polypeptide NTCP/SLC10A1 is important for the uptake of bile salts and selected drugs. Its inhibition results in increased systemic bile salt concentrations. NTCP is also the entry receptor for the hepatitis B/D virus. We investigated interindividual hepatic SLC10A1/NTCP expression using various omics technologies. SLC10A1/NTCP mRNA expression/protein abundance was quantified in well-characterized 143 human livers by real-time PCR and LC-MS/MS-based targeted proteomics. Genome-wide SNP arrays and SLC10A1 next-generation sequencing were used for genomic analyses. SLC10A1 DNA methylation was assessed through MALDI-TOF MS. Transcriptomics and untargeted metabolomics (UHPLC-Q-TOF-MS) were correlated to identify NTCP-related metabolic pathways. SLC10A1 mRNA and NTCP protein levels varied 44-fold and 10.4-fold, respectively. Non-genetic factors (e.g., smoking, alcohol consumption) influenced significantly NTCP expression. Genetic variants in SLC10A1 or other genes do not explain expression variability which was validated in livers (n = 50) from The Cancer Genome Atlas. The identified two missense SLC10A1 variants did not impair transport function in transfectants. Specific CpG sites in SLC10A1 as well as single metabolic alterations and pathways (e.g., peroxisomal and bile acid synthesis) were significantly associated with expression. Inter-individual variability of NTCP expression is multifactorial with the contribution of clinical factors, DNA methylation, transcriptional regulation as well as hepatic metabolism, but not genetic variation. Full article

(This article belongs to the Special Issue Overcoming Biological Barriers: Importance of Membrane Transporters in Homeostasis, Disease, and Disease Treatment)

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24 pages, 13027 KiB

Open AccessArticle

Generalized Approach towards Secretion-Based Protein Production via Neutralization of Secretion-Preventing Cationic Substrate Residues

by Hyunjong Byun, Jiyeon Park, Benedict U. Fabia, Joshua Bingwa, Mihn Hieu Nguyen, Haeshin Lee and Jung Hoon Ahn

Int. J. Mol. Sci. 2022, 23(12), 6700; https://doi.org/10.3390/ijms23126700 - 15 Jun 2022

Cited by 3 | Viewed by 1943

Abstract

Many heterologous proteins can be secreted by bacterial ATP-binding cassette (ABC) transporters, provided that they are fused with the C-terminal signal sequence, but some proteins are not secretable even though they carry the right signal sequence. The invention of a method to secrete [...] Read more.

Many heterologous proteins can be secreted by bacterial ATP-binding cassette (ABC) transporters, provided that they are fused with the C-terminal signal sequence, but some proteins are not secretable even though they carry the right signal sequence. The invention of a method to secrete these non-secretable proteins would be valuable both for understanding the secretory physiology of ABC transporters and for industrial applications. Herein, we postulate that cationic “supercharged” regions within the target substrate protein block the secretion by ABC transporters. We also suggest that the secretion of such substrate proteins can be rescued by neutralizing those cationic supercharged regions via structure-preserving point mutageneses. Surface-protruding, non-structural cationic amino acids within the cationic supercharged regions were replaced by anionic or neutral hydrophilic amino acids, reducing the cationic charge density. The examples of rescued secretions we provide include the spike protein of SARS-CoV-2, glutathione-S-transferase, streptavidin, lipase, tyrosinase, cutinase, growth factors, etc. In summary, our study provides a method to predict the secretability and a tool to rescue the secretion by correcting the secretion-blocking regions, making a significant step in understanding the physiological properties of ABC transporter-dependent protein secretion and laying the foundation for the development of a secretion-based protein-producing platform. Full article

(This article belongs to the Special Issue Overcoming Biological Barriers: Importance of Membrane Transporters in Homeostasis, Disease, and Disease Treatment)

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12 pages, 1237 KiB

Open AccessArticle

Use of PET Imaging to Assess the Efficacy of Thiethylperazine to Stimulate Cerebral MRP1 Transport Activity in Wild-Type and APP/PS1-21 Mice

by Michael Wölfl-Duchek, Severin Mairinger, Irene Hernández-Lozano, Thomas Filip, Viktoria Zoufal, Mathilde Löbsch, Johann Stanek, Claudia Kuntner, Thomas Wanek, Martin Bauer, Jens Pahnke and Oliver Langer

Int. J. Mol. Sci. 2022, 23(12), 6514; https://doi.org/10.3390/ijms23126514 - 10 Jun 2022

Cited by 2 | Viewed by 2712

Abstract

Multidrug resistance-associated protein 1 (MRP1, encoded by the ABCC1 gene) may contribute to the clearance of amyloid-beta (Aβ) peptides from the brain into the blood and stimulation of MRP1 transport activity may be a therapeutic approach to enhance brain Aβ clearance. In this [...] Read more.

Multidrug resistance-associated protein 1 (MRP1, encoded by the ABCC1 gene) may contribute to the clearance of amyloid-beta (Aβ) peptides from the brain into the blood and stimulation of MRP1 transport activity may be a therapeutic approach to enhance brain Aβ clearance. In this study, we assessed the effect of thiethylperazine, an antiemetic drug which was shown to stimulate MRP1 activity in vitro and to decrease Aβ load in a rapid β-amyloidosis mouse model (APP/PS1-21), on MRP1 transport activity by means of positron emission tomography (PET) imaging with the MRP1 tracer 6-bromo-7-[¹¹C]methylpurine. Groups of wild-type, APP/PS1-21 and Abcc1^(−/−) mice underwent PET scans before and after a 5-day oral treatment period with thiethylperazine (15 mg/kg, once daily). The elimination rate constant of radioactivity (k_elim) was calculated from time–activity curves in the brain and the lungs as a measure of tissue MRP1 activity. Treatment with thiethylperazine had no significant effect on MRP1 activity in the brain and the lungs of wild-type and APP/PS1-21 mice. This may either be related to a lack of an MRP1-stimulating effect of thiethylperazine in vivo or to other factors, such as substrate-dependent MRP1 stimulation, insufficient target tissue exposure to thiethylperazine or limited sensitivity of the PET tracer to measure MRP1 stimulation. Full article

(This article belongs to the Special Issue Overcoming Biological Barriers: Importance of Membrane Transporters in Homeostasis, Disease, and Disease Treatment)

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15 pages, 3262 KiB

Open AccessArticle

Pharmacological Effects of Panduratin A on Renal Cyst Development in In Vitro and In Vivo Models of Polycystic Kidney Disease

by Kanlayanee Tonum, Nipitpon Srimai, Napason Chabang, Somsak Fongsupa, Patoomratana Tuchinda, Jacob A. Torres, Thomas Weimbs and Sunhapas Soodvilai

Int. J. Mol. Sci. 2022, 23(8), 4328; https://doi.org/10.3390/ijms23084328 - 14 Apr 2022

Cited by 3 | Viewed by 2489

Abstract

Renal cyst expansion in polycystic kidney disease (PKD) involves abnormalities in both cyst-lining-cell proliferation and fluid accumulation. Suppression of these processes may retard the progression of PKD. Evidence suggests that the activation of 5′ AMP-activated protein kinase (AMPK) inhibits cystic fibrosis transmembrane conductance [...] Read more.

Renal cyst expansion in polycystic kidney disease (PKD) involves abnormalities in both cyst-lining-cell proliferation and fluid accumulation. Suppression of these processes may retard the progression of PKD. Evidence suggests that the activation of 5′ AMP-activated protein kinase (AMPK) inhibits cystic fibrosis transmembrane conductance regulator (CFTR)–mediated chloride secretion, leading to reduced progression of PKD. Here we investigated the pharmacological effects of panduratin A, a bioactive compound known as an AMPK activator, on CFTR-mediated chloride secretion and renal cyst development using in vitro and animal models of PKD. We demonstrated that AMPK was activated in immortalized normal renal cells and autosomal dominant polycystic kidney disease (ADPKD) cells following treatment with panduratin A. Treatment with panduratin A reduced the number of renal cyst colonies corresponding with a decrease in cell proliferation and phosphorylated p70/S6K, a downstream target of mTOR signaling. Additionally, panduratin A slowed cyst expansion via inhibition of the protein expression and transport function of CFTR. In heterozygous Han:Sprague–Dawley (Cy/+) rats, an animal model of PKD, intraperitoneal administration of panduratin A (25 mg/kg BW) for 5 weeks significantly decreased the kidney weight per body weight ratios and the cystic index. Panduratin A also reduced collagen deposition in renal tissue. Intraperitoneal administration of panduratin A caused abdominal bleeding and reduced body weight. However, 25 mg/kg BW of panduratin A via oral administration in the PCK rats, another non-orthologous PKD model, showed a significant decrease in the cystic index without severe adverse effects, indicating that the route of administration is critical in preventing adverse effects while still slowing disease progression. These findings reveal that panduratin A might hold therapeutic properties for the treatment of PKD. Full article

(This article belongs to the Special Issue Overcoming Biological Barriers: Importance of Membrane Transporters in Homeostasis, Disease, and Disease Treatment)

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9 pages, 1827 KiB

Open AccessArticle

An Efficient Way to Screen Inhibitors of Energy-Coupling Factor (ECF) Transporters in a Bacterial Uptake Assay

by Spyridon Bousis, Steffen Winkler, Jörg Haupenthal, Francesco Fulco, Eleonora Diamanti and Anna K. H. Hirsch

Int. J. Mol. Sci. 2022, 23(5), 2637; https://doi.org/10.3390/ijms23052637 - 27 Feb 2022

Cited by 5 | Viewed by 1792

Abstract

Herein, we report a novel whole-cell screening assay using Lactobacillus casei as a model microorganism to identify inhibitors of energy-coupling factor (ECF) transporters. This promising and underexplored target may have important pharmacological potential through modulation of vitamin homeostasis in bacteria and, importantly, it [...] Read more.

Herein, we report a novel whole-cell screening assay using Lactobacillus casei as a model microorganism to identify inhibitors of energy-coupling factor (ECF) transporters. This promising and underexplored target may have important pharmacological potential through modulation of vitamin homeostasis in bacteria and, importantly, it is absent in humans. The assay represents an alternative, cost-effective and fast solution to demonstrate the direct involvement of these membrane transporters in a native biological environment rather than using a low-throughput in vitro assay employing reconstituted proteins in a membrane bilayer system. Based on this new whole-cell screening approach, we demonstrated the optimization of a weak hit compound (2) into a small molecule (3) with improved in vitro and whole-cell activities. This study opens the possibility to quickly identify novel inhibitors of ECF transporters and optimize them based on structure–activity relationships. Full article

(This article belongs to the Special Issue Overcoming Biological Barriers: Importance of Membrane Transporters in Homeostasis, Disease, and Disease Treatment)

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20 pages, 7269 KiB

Open AccessArticle

Relationships between Inhibition, Transport and Enhanced Transport via the Organic Cation Transporter 1

by Ole Jensen, Lukas Gebauer, Jürgen Brockmöller and Christof Dücker

Int. J. Mol. Sci. 2022, 23(4), 2007; https://doi.org/10.3390/ijms23042007 - 11 Feb 2022

Cited by 12 | Viewed by 1883

Abstract

The organic cation transporter 1 (OCT1, SLC22A1) transports a large number of structurally diverse endogenous and exogenous substrates. There are numerous known competitive and non-competitive inhibitors of OCT1, but there are no studies systematically analyzing the relationship between transport, stimulation, and inhibition. [...] Read more.

The organic cation transporter 1 (OCT1, SLC22A1) transports a large number of structurally diverse endogenous and exogenous substrates. There are numerous known competitive and non-competitive inhibitors of OCT1, but there are no studies systematically analyzing the relationship between transport, stimulation, and inhibition. Here, we tested in vitro OCT1 inhibition by OCT1 substrates and transport of OCT1 inhibitors under uniform analytical conditions. Beyond inhibition testing with two model substrates, we tested nine additional OCT1 substrates for their mutual inhibition. Inhibition of ASP⁺ uptake by most OCT1 substrates was weak. The model substrate sumatriptan, with its moderately stronger inhibitability, was used to confirm this. Interestingly, OCT1 substrates exhibiting stronger OCT1 inhibition were mainly biaromatic β-agonistic drugs, such as dobutamine, fenoterol, ractopamine and ritodrine. Biaromatic organic cations were both, strong inhibitors and good substrates, but many OCT1 substrates showed little pairwise inhibition. Surprisingly, sumatriptan did significantly enhance dobutamine uptake. This effect was concentration dependent and additional experiments indicated that efflux inhibition may be one of the underlying mechanisms. Our data suggests, that OCT1 substrates are mainly weak OCT1 inhibitors and among those inhibiting well, noncompetitive inhibition could be responsible. Weak competitive inhibition confirms that OCT1 inhibition screenings poorly predict OCT1 substrates. Additionally, we showed that the OCT1 substrate sumatriptan can enhance uptake of some other OCT1 substrates. OCT1 transport stimulation was already observed earlier but is still poorly understood. Low OCT1 uptake inhibition and strong OCT1 efflux inhibition could be mechanisms exploitable for enhancing transport. Full article

(This article belongs to the Special Issue Overcoming Biological Barriers: Importance of Membrane Transporters in Homeostasis, Disease, and Disease Treatment)

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Review

Jump to: Editorial, Research

24 pages, 403 KiB

Open AccessReview

The Role of Organic Cation Transporters in the Pharmacokinetics, Pharmacodynamics and Drug–Drug Interactions of Tyrosine Kinase Inhibitors

by Fangrui Xiu, Magdalena Rausch, Zhibo Gai, Shanshan Su, Shijun Wang and Michele Visentin

Int. J. Mol. Sci. 2023, 24(3), 2101; https://doi.org/10.3390/ijms24032101 - 20 Jan 2023

Cited by 2 | Viewed by 1983

Abstract

Tyrosine kinase inhibitors (TKIs) decisively contributed in revolutionizing the therapeutic approach to cancer, offering non-invasive, tolerable therapies for a better quality of life. Nonetheless, degree and duration of the response to TKI therapy vary depending on cancer molecular features, the ability of developing [...] Read more.

Tyrosine kinase inhibitors (TKIs) decisively contributed in revolutionizing the therapeutic approach to cancer, offering non-invasive, tolerable therapies for a better quality of life. Nonetheless, degree and duration of the response to TKI therapy vary depending on cancer molecular features, the ability of developing resistance to the drug, on pharmacokinetic alterations caused by germline variants and unwanted drug–drug interactions at the level of membrane transporters and metabolizing enzymes. A great deal of approved TKIs are inhibitors of the organic cation transporters (OCTs). A handful are also substrates of them. These transporters are polyspecific and highly expressed in normal epithelia, particularly the intestine, liver and kidney, and are, hence, arguably relevant sites of TKI interactions with other OCT substrates. Moreover, OCTs are often repressed in cancer cells and might contribute to the resistance of cancer cells to TKIs. This article reviews the OCT interactions with approved and in-development TKIs reported in vitro and in vivo and critically discusses the potential clinical ramifications thereof. Full article

(This article belongs to the Special Issue Overcoming Biological Barriers: Importance of Membrane Transporters in Homeostasis, Disease, and Disease Treatment)

17 pages, 1680 KiB

Open AccessReview

Inborn Errors of Nucleoside Transporter (NT)-Encoding Genes (SLC28 and SLC29)

by Marçal Pastor-Anglada, Aida Mata-Ventosa and Sandra Pérez-Torras

Int. J. Mol. Sci. 2022, 23(15), 8770; https://doi.org/10.3390/ijms23158770 - 07 Aug 2022

Cited by 4 | Viewed by 2088

Abstract

The proper regulation of nucleotide pools is essential for all types of cellular functions and depends on de novo nucleotide biosynthesis, salvage, and degradation pathways. Despite the apparent essentiality of these processes, a significant number of rare diseases associated with mutations in genes [...] Read more.

The proper regulation of nucleotide pools is essential for all types of cellular functions and depends on de novo nucleotide biosynthesis, salvage, and degradation pathways. Despite the apparent essentiality of these processes, a significant number of rare diseases associated with mutations in genes encoding various enzymes of these pathways have been already identified, and others are likely yet to come. However, knowledge on genetic alterations impacting on nucleoside and nucleobase transporters is still limited. At this moment three gene-encoding nucleoside and nucleobase transporter proteins have been reported to be mutated in humans, SLC29A1, SLC29A3, and SLC28A1, impacting on the expression and function of ENT1, ENT3, and CNT1, respectively. ENT1 alterations determine Augustine-null blood type and cause ectopic calcification during aging. ENT3 deficiency translates into various clinical manifestations and syndromes, altogether listed in the OMIM catalog as histiocytosis-lymphoadenopathy plus syndrome (OMIM#602782). CNT1 deficiency causes uridine-cytidineuria (URCTU) (OMIM#618477), a unique type of pyrimidineuria with an as yet not well-known clinical impact. Increasing knowledge on the physiological, molecular and structural features of these transporter proteins is helping us to better understand the biological basis behind the biochemical and clinical manifestations caused by these deficiencies. Moreover, they also support the view that some metabolic compensation might occur in these disturbances, because they do not seem to significantly impact nucleotide homeostasis, but rather other biological events associated with particular subtypes of transporter proteins. Full article

(This article belongs to the Special Issue Overcoming Biological Barriers: Importance of Membrane Transporters in Homeostasis, Disease, and Disease Treatment)

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15 pages, 850 KiB

Open AccessReview

Importance of GLUT Transporters in Disease Diagnosis and Treatment

by Abdelrahman Ismail and Marina Tanasova

Int. J. Mol. Sci. 2022, 23(15), 8698; https://doi.org/10.3390/ijms23158698 - 04 Aug 2022

Cited by 18 | Viewed by 3932

Abstract

Facilitative sugar transporters (GLUTs) are the primary method of sugar uptake in all mammalian cells. There are 14 different types of those transmembrane proteins, but they transport only a handful of substrates, mainly glucose and fructose. This overlap and redundancy contradict the natural [...] Read more.

Facilitative sugar transporters (GLUTs) are the primary method of sugar uptake in all mammalian cells. There are 14 different types of those transmembrane proteins, but they transport only a handful of substrates, mainly glucose and fructose. This overlap and redundancy contradict the natural tendency of cells to conserve energy and resources, and has led researchers to hypothesize that different GLUTs partake in more metabolic roles than just sugar transport into cells. Understanding those roles will lead to better therapeutics for a wide variety of diseases and disorders. In this review we highlight recent discoveries of the role GLUTs play in different diseases and disease treatments. Full article

(This article belongs to the Special Issue Overcoming Biological Barriers: Importance of Membrane Transporters in Homeostasis, Disease, and Disease Treatment)

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14 pages, 1692 KiB

Open AccessReview

TM4SF5-Mediated Regulation of Hepatocyte Transporters during Metabolic Liver Diseases

by Ji Eon Kim, Eunmi Kim and Jung Weon Lee

Int. J. Mol. Sci. 2022, 23(15), 8387; https://doi.org/10.3390/ijms23158387 - 29 Jul 2022

Cited by 2 | Viewed by 2440

Abstract

Nonalcoholic fatty liver disease (NAFLD) is found in up to 30% of the world’s population and can lead to hepatocellular carcinoma (HCC), which has a poor 5-year relative survival rate of less than 40%. Clinical therapeutic strategies are not very successful. The co-occurrence [...] Read more.

Nonalcoholic fatty liver disease (NAFLD) is found in up to 30% of the world’s population and can lead to hepatocellular carcinoma (HCC), which has a poor 5-year relative survival rate of less than 40%. Clinical therapeutic strategies are not very successful. The co-occurrence of metabolic disorders and inflammatory environments during the development of steatohepatitis thus needs to be more specifically diagnosed and treated to prevent fatal HCC development. To improve diagnostic and therapeutic strategies, the identification of molecules and/or pathways responsible for the initiation and progression of chronic liver disease has been explored in many studies, but further study is still required. Transmembrane 4 L six family member 5 (TM4SF5) has been observed to play roles in the regulation of metabolic functions and activities in hepatocytes using in vitro cell and in vivo animal models without or with TM4SF5 expression in addition to clinical liver tissue samples. TM4SF5 is present on the membranes of different organelles or vesicles and cooperates with transporters for fatty acids, amino acids, and monocarbohydrates, thus regulating nutrient uptake into hepatocytes and metabolism and leading to phenotypes of chronic liver diseases. In addition, TM4SF5 can remodel the immune environment by interacting with immune cells during TM4SF5-mediated chronic liver diseases. Because TM4SF5 may act as an NAFLD biomarker, this review summarizes crosstalk between TM4SF5 and nutrient transporters in hepatocytes, which is related to chronic liver diseases. Full article

(This article belongs to the Special Issue Overcoming Biological Barriers: Importance of Membrane Transporters in Homeostasis, Disease, and Disease Treatment)

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