Atorvastatin Increases miR-124a Expression: A Mechanism of Gamt Modulation in Liver Cells

ABSTRACT Atorvastatin is used to control cholesterol and lipid levels in hyperlipidaemic and hypercholesterolaemic patients. Myopathy and hepatotoxicity, however, have been reported as side effects in a small percentage of statin users. This study aimed to investigate the cytotoxicity and the effect...

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Veröffentlicht in:Journal of cellular biochemistry 2015-11, Vol.116 (11), p.2620-2627
Hauptverfasser: Phulukdaree, Alisa, Moodley, Devapregasan, Khan, Sajidah, Chuturgoon, Anil A.
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container_end_page 2627
container_issue 11
container_start_page 2620
container_title Journal of cellular biochemistry
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creator Phulukdaree, Alisa
Moodley, Devapregasan
Khan, Sajidah
Chuturgoon, Anil A.
description ABSTRACT Atorvastatin is used to control cholesterol and lipid levels in hyperlipidaemic and hypercholesterolaemic patients. Myopathy and hepatotoxicity, however, have been reported as side effects in a small percentage of statin users. This study aimed to investigate the cytotoxicity and the effect of atorvastatin on microRNA expression in HepG2 cells. The methylthiazol tetrazolium assay was used to assess hepatocyte viability and at 20 μM atorvastatin (24 h) treatment were 82 ± 1.5% viable (P = 0.0002). Levels of intracellular ATP in cells treated with 20 μM atorvastatin were reduced by 1.25‐fold, P = 0.002. Cytotoxicity, measured by the release of intracellular lactate dehydrogenase, was increased from 0.95 ± 0.29 units in control cells to 1.12 ± 0.02 units (P = 0.002) in atorvastatin treated cells. A panel of 84‐miRNA species was used to evaluate the effect of atorvastatin on miRNA expression. MiR‐124a was significantly up‐regulated by atorvastatin (12.94‐fold). A significant decrease in GAMT expression (3.54‐fold) was observed in atorvastatin treated cells following quantitative PCR analysis. In addition, western blotting data showed GAMT protein levels were significantly lower than the controls (3.02‐fold) and analysis of creatine levels in treated cells showed a significant decrease in the atorvastatin treated culture supernatant compared to control culture supernatant (32.33 ± 3.51 μM/l vs. 59.67 ± 1.52μM/l, P = 0.0056). This is the first study to show that atorvastatin up‐regulates miR‐124a levels and consequently modulates GAMT expression in hepatocytes. J. Cell. Biochem. 116: 2620–2627, 2015. © 2015 Wiley Periodicals, Inc.
doi_str_mv 10.1002/jcb.25209
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Myopathy and hepatotoxicity, however, have been reported as side effects in a small percentage of statin users. This study aimed to investigate the cytotoxicity and the effect of atorvastatin on microRNA expression in HepG2 cells. The methylthiazol tetrazolium assay was used to assess hepatocyte viability and at 20 μM atorvastatin (24 h) treatment were 82 ± 1.5% viable (P = 0.0002). Levels of intracellular ATP in cells treated with 20 μM atorvastatin were reduced by 1.25‐fold, P = 0.002. Cytotoxicity, measured by the release of intracellular lactate dehydrogenase, was increased from 0.95 ± 0.29 units in control cells to 1.12 ± 0.02 units (P = 0.002) in atorvastatin treated cells. A panel of 84‐miRNA species was used to evaluate the effect of atorvastatin on miRNA expression. MiR‐124a was significantly up‐regulated by atorvastatin (12.94‐fold). A significant decrease in GAMT expression (3.54‐fold) was observed in atorvastatin treated cells following quantitative PCR analysis. In addition, western blotting data showed GAMT protein levels were significantly lower than the controls (3.02‐fold) and analysis of creatine levels in treated cells showed a significant decrease in the atorvastatin treated culture supernatant compared to control culture supernatant (32.33 ± 3.51 μM/l vs. 59.67 ± 1.52μM/l, P = 0.0056). This is the first study to show that atorvastatin up‐regulates miR‐124a levels and consequently modulates GAMT expression in hepatocytes. J. Cell. 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Cell. Biochem</addtitle><description>ABSTRACT Atorvastatin is used to control cholesterol and lipid levels in hyperlipidaemic and hypercholesterolaemic patients. Myopathy and hepatotoxicity, however, have been reported as side effects in a small percentage of statin users. This study aimed to investigate the cytotoxicity and the effect of atorvastatin on microRNA expression in HepG2 cells. The methylthiazol tetrazolium assay was used to assess hepatocyte viability and at 20 μM atorvastatin (24 h) treatment were 82 ± 1.5% viable (P = 0.0002). Levels of intracellular ATP in cells treated with 20 μM atorvastatin were reduced by 1.25‐fold, P = 0.002. Cytotoxicity, measured by the release of intracellular lactate dehydrogenase, was increased from 0.95 ± 0.29 units in control cells to 1.12 ± 0.02 units (P = 0.002) in atorvastatin treated cells. A panel of 84‐miRNA species was used to evaluate the effect of atorvastatin on miRNA expression. MiR‐124a was significantly up‐regulated by atorvastatin (12.94‐fold). A significant decrease in GAMT expression (3.54‐fold) was observed in atorvastatin treated cells following quantitative PCR analysis. In addition, western blotting data showed GAMT protein levels were significantly lower than the controls (3.02‐fold) and analysis of creatine levels in treated cells showed a significant decrease in the atorvastatin treated culture supernatant compared to control culture supernatant (32.33 ± 3.51 μM/l vs. 59.67 ± 1.52μM/l, P = 0.0056). This is the first study to show that atorvastatin up‐regulates miR‐124a levels and consequently modulates GAMT expression in hepatocytes. J. Cell. 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subjects 3' Untranslated Regions
Adenosine Triphosphate - metabolism
Anticholesteremic Agents - pharmacology
ATORVASTATIN
Atorvastatin Calcium - pharmacology
Cell culture
Cell Proliferation - drug effects
Cell Survival - drug effects
Cholesterol
CREATINE
Creatinine - metabolism
Cytotoxicity
Guanidinoacetate N-Methyltransferase - genetics
Guanidinoacetate N-Methyltransferase - metabolism
GUANIDINOACETATE-N-METHYLTRANSFERASE
Hep G2 Cells
Hepatocytes
HEPATOTOXICITY
Humans
Intracellular
L-Lactate dehydrogenase
Lactate dehydrogenase
Lactic acid
Lipids
MicroRNAs
MicroRNAs - genetics
miRNA
Myopathy
Protein folding
Ribonucleic acid
RNA
Side effects
Statins
Toxicity
Up-Regulation
Western blotting
title Atorvastatin Increases miR-124a Expression: A Mechanism of Gamt Modulation in Liver Cells
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