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Atorvastatin increases miR-124a expression: a mechanism of Gamt modulation in liver cells

Alisa Phulukdaree1, Devapregasan Moodley2, Sajidah Khan2

  • 1Department of Physiology, College of Health Sciences, University of Pretoria, Durban, South Africa.

Journal of Cellular Biochemistry
|May 1, 2015
PubMed

Insights

This study investigated atorvastatin

Area of Science:

  • Hepatology and molecular biology
  • Pharmacology and toxicology

Background:

  • Atorvastatin is a widely prescribed statin for managing hyperlipidemia.
  • Potential side effects include myopathy and hepatotoxicity, necessitating further investigation into its cellular effects.
  • Understanding atorvastatin's impact on liver cells (HepG2) and microRNA (miRNA) expression is crucial.

Purpose of the Study:

  • To assess the cytotoxicity of atorvastatin in HepG2 cells.
  • To investigate the effect of atorvastatin on miRNA expression profiles in hepatocytes.
  • To explore the molecular mechanisms underlying atorvastatin's cellular effects, focusing on GAMT expression.

Main Methods:

  • Cytotoxicity was evaluated using methylthiazol tetrazolium (MTT) assays to measure cell viability and lactate dehydrogenase (LDH) release.
  • Intracellular adenosine triphosphate (ATP) levels were quantified.
  • A panel of 84 miRNA species was analyzed, with specific attention to miR-124a, and gene/protein expression of Guanidinoacetate N-methyltransferase (GAMT) was assessed via quantitative PCR and Western blotting. Creatine levels were also measured.

Main Results:

  • Atorvastatin treatment at 20 μM for 24 hours resulted in reduced HepG2 cell viability (82%) and increased cytotoxicity.
  • Intracellular ATP levels decreased by 1.25-fold, and LDH release increased significantly.
  • Atorvastatin significantly upregulated miR-124a (12.94-fold) and downregulated GAMT expression and protein levels (3.54-fold and 3.02-fold, respectively), accompanied by a decrease in creatine levels in the supernatant.

Conclusions:

  • Atorvastatin exhibits cytotoxicity in HepG2 cells at 20 μM.
  • The study demonstrates for the first time that atorvastatin upregulates miR-124a in hepatocytes.
  • This upregulation of miR-124a is associated with the modulation of GAMT expression and creatine metabolism, suggesting a novel mechanism of action for atorvastatin's cellular effects.
Keywords:
ATORVASTATINCREATINEGUANIDINOACETATE-N-METHYLTRANSFERASEHEPATOTOXICITY

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