Monocarboxylate Transporter 1 (MCT1) in Liver Pathology

Overview

Journal Int J Mol Sci

Publisher MDPI

Specialties Biochemistry
Chemistry
Molecular Biology

Date 2020 Mar 1

PMID 32111097

Citations 10

Authors

Marek Drozdzik

Sylwia Szelag-Pieniek

Justyna Grzegolkowska

Joanna Lapczuk-Romanska

Mariola Post

Pawel Domagala

Janusz Mietkiewski

Stefan Oswald

Mateusz Kurzawski

Affiliations

Soon will be listed here.

Abstract

Membrane monocarboxylate transporter 1 (/MCT1) plays an important role in hepatocyte homeostasis, as well as drug handling. However, there is no available information about the impact of liver pathology on the transporter levels and function. The study was aimed to quantify mRNA (qRT-PCR) and MCT1 protein abundance (liquid chromatography-tandem mass spectrometry (LC---MS/MS)) in the livers of patients diagnosed, according to the standard clinical criteria, with hepatitis C, primary biliary cirrhosis, primary sclerosing hepatitis, alcoholic liver disease (ALD), and autoimmune hepatitis. The stage of liver dysfunction was classified according to Child-Pugh score. Downregulation of /MCT1 levels was observed in all liver pathology states, significantly for ALD. The progression of liver dysfunction, from Child-Pugh class A to C, involved the gradual decline in mRNA and MCT1 protein abundance, reaching a clinically significant decrease in class C livers. Reduced levels of MCT1 were associated with significant intracellular lactate accumulation. The MCT1 transcript and protein did not demonstrate significant correlations regardless of the liver pathology analyzed, as well as the disease stage, suggesting posttranscriptional regulation, and several microRNAs were found as potential regulators of MCT1 abundance. MCT1 membrane immunolocalization without cytoplasmic retention was observed in all studied liver pathologies. Overall, the study demonstrates that /MCT1 is involved in liver pathology, especially in ALD.

Citing Articles

The Role of Solute Carrier Family Transporters in Hepatic Steatosis and Hepatic Fibrosis.

Zhang C, Yang X, Xue Y, Li H, Zeng C, Chen M J Clin Transl Hepatol. 2025; 13(3):233-252.

PMID: 40078199 PMC: 11894391. DOI: 10.14218/JCTH.2024.00348.

Lactate and lactylation in cancer.

Chen J, Huang Z, Chen Y, Tian H, Chai P, Shen Y Signal Transduct Target Ther. 2025; 10(1):38.

PMID: 39934144 PMC: 11814237. DOI: 10.1038/s41392-024-02082-x.

Progress in Lactate Metabolism and Its Regulation via Small Molecule Drugs.

Liu J, Zhou F, Tang Y, Li L, Li L Molecules. 2024; 29(23).

PMID: 39683818 PMC: 11643809. DOI: 10.3390/molecules29235656.

Exploring SLC16A1 as an Oncogenic Regulator and Therapeutic Target in Cholangiocarcinoma.

Huang J, Liu F, Liu D, Tang S, Shen D J Cancer. 2024; 15(12):3794-3808.

PMID: 38911368 PMC: 11190756. DOI: 10.7150/jca.95258.

Role of lactate and lactate metabolism in liver diseases (Review).

Yao S, Chai H, Tao T, Zhang L, Yang X, Li X Int J Mol Med. 2024; 54(1).

PMID: 38785162 PMC: 11188982. DOI: 10.3892/ijmm.2024.5383.

References

Morse B, Felmlee M, Morris M . γ-Hydroxybutyrate blood/plasma partitioning: effect of physiologic pH on transport by monocarboxylate transporters. Drug Metab Dispos. 2011; 40(1):64-9. PMC: 3250051. DOI: 10.1124/dmd.111.041285. View

Wilson M, Meredith D, Manning Fox J, Manoharan C, Davies A, Halestrap A . Basigin (CD147) is the target for organomercurial inhibition of monocarboxylate transporter isoforms 1 and 4: the ancillary protein for the insensitive MCT2 is EMBIGIN (gp70). J Biol Chem. 2005; 280(29):27213-21. DOI: 10.1074/jbc.M411950200. View

Mehibel M, Ortiz-Martinez F, Voelxen N, Boyers A, Chadwick A, Telfer B . Statin-induced metabolic reprogramming in head and neck cancer: a biomarker for targeting monocarboxylate transporters. Sci Rep. 2018; 8(1):16804. PMC: 6235971. DOI: 10.1038/s41598-018-35103-1. View

Hou L, Zhao Y, Song G, Ma Y, Jin X, Jin S . Interfering cellular lactate homeostasis overcomes Taxol resistance of breast cancer cells through the microRNA-124-mediated lactate transporter (MCT1) inhibition. Cancer Cell Int. 2019; 19:193. PMC: 6657142. DOI: 10.1186/s12935-019-0904-0. View

Polanski R, Hodgkinson C, Fusi A, Nonaka D, Priest L, Kelly P . Activity of the monocarboxylate transporter 1 inhibitor AZD3965 in small cell lung cancer. Clin Cancer Res. 2013; 20(4):926-937. PMC: 3929348. DOI: 10.1158/1078-0432.CCR-13-2270. View

Wang Y, Hu C, Cheng J, Chen B, Ke Q, Lv Z . MicroRNA-145 suppresses hepatocellular carcinoma by targeting IRS1 and its downstream Akt signaling. Biochem Biophys Res Commun. 2014; 446(4):1255-60. DOI: 10.1016/j.bbrc.2014.03.107. View

Philp N, Wang D, Yoon H, Hjelmeland L . Polarized expression of monocarboxylate transporters in human retinal pigment epithelium and ARPE-19 cells. Invest Ophthalmol Vis Sci. 2003; 44(4):1716-21. DOI: 10.1167/iovs.02-0287. View

Wisniewski J, Zougman A, Nagaraj N, Mann M . Universal sample preparation method for proteome analysis. Nat Methods. 2009; 6(5):359-62. DOI: 10.1038/nmeth.1322. View

Halestrap A, Wilson M . The monocarboxylate transporter family--role and regulation. IUBMB Life. 2011; 64(2):109-19. DOI: 10.1002/iub.572. View

10.

Pullen T, da Silva Xavier G, Kelsey G, Rutter G . miR-29a and miR-29b contribute to pancreatic beta-cell-specific silencing of monocarboxylate transporter 1 (Mct1). Mol Cell Biol. 2011; 31(15):3182-94. PMC: 3147603. DOI: 10.1128/MCB.01433-10. View

11.

Kurzawski M, Szelag-Pieniek S, Lapczuk-Romanska J, Wrzesinski M, Sienko J, Oswald S . The reference liver - ABC and SLC drug transporters in healthy donor and metastatic livers. Pharmacol Rep. 2019; 71(4):738-745. DOI: 10.1016/j.pharep.2019.04.001. View

12.

Strazzabosco M, Boyer J . Regulation of intracellular pH in the hepatocyte. Mechanisms and physiological implications. J Hepatol. 1996; 24(5):631-44. DOI: 10.1016/s0168-8278(96)80153-x. View

13.

Pellerin L, Magistretti P . Sweet sixteen for ANLS. J Cereb Blood Flow Metab. 2011; 32(7):1152-66. PMC: 3390819. DOI: 10.1038/jcbfm.2011.149. View

14.

Romero-Cordoba S, Rodriguez-Cuevas S, Bautista-Pina V, Maffuz-Aziz A, DIppolito E, Cosentino G . Loss of function of miR-342-3p results in MCT1 over-expression and contributes to oncogenic metabolic reprogramming in triple negative breast cancer. Sci Rep. 2018; 8(1):12252. PMC: 6095912. DOI: 10.1038/s41598-018-29708-9. View

15.

Halestrap A, Meredith D . The SLC16 gene family-from monocarboxylate transporters (MCTs) to aromatic amino acid transporters and beyond. Pflugers Arch. 2003; 447(5):619-28. DOI: 10.1007/s00424-003-1067-2. View

16.

Zhang J, Cao Z, Yang G, You L, Zhang T, Zhao Y . MicroRNA-27a (miR-27a) in Solid Tumors: A Review Based on Mechanisms and Clinical Observations. Front Oncol. 2019; 9:893. PMC: 6751266. DOI: 10.3389/fonc.2019.00893. View

17.

Schofield Z, Reed M, Newsome P, Adams D, Gunther U, Lalor P . Changes in human hepatic metabolism in steatosis and cirrhosis. World J Gastroenterol. 2017; 23(15):2685-2695. PMC: 5403747. DOI: 10.3748/wjg.v23.i15.2685. View

18.

Fisel P, Schaeffeler E, Schwab M . Clinical and Functional Relevance of the Monocarboxylate Transporter Family in Disease Pathophysiology and Drug Therapy. Clin Transl Sci. 2018; 11(4):352-364. PMC: 6039204. DOI: 10.1111/cts.12551. View

19.

Marchiq I, Pouyssegur J . Hypoxia, cancer metabolism and the therapeutic benefit of targeting lactate/H(+) symporters. J Mol Med (Berl). 2015; 94(2):155-71. PMC: 4762928. DOI: 10.1007/s00109-015-1307-x. View

20.

Bruckmueller H, Martin P, Kahler M, Haenisch S, Ostrowski M, Drozdzik M . Clinically Relevant Multidrug Transporters Are Regulated by microRNAs along the Human Intestine. Mol Pharm. 2017; 14(7):2245-2253. DOI: 10.1021/acs.molpharmaceut.7b00076. View