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Inhibitors of AKT kinase increase LDL receptor mRNA expression by two different mechanisms

Katrine Bjune1, Lene Wierød1, Soheil Naderi1

  • 1Unit for Cardiac and Cardiovascular Genetics, Department of Medical Genetics, Oslo University Hospital, Oslo, Norway.

Plos One
|June 20, 2019
PubMed

Insights

Protein kinase B (AKT) inhibitors increase low-density lipoprotein receptor (LDLR) mRNA levels. This study confirms AKT

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Pharmacology

Background:

  • Protein kinase B (AKT) is a key signaling molecule downstream of phosphoinositide 3-kinase.
  • Previous studies indicated AKT inhibitors affect low-density lipoprotein receptor (LDLR) mRNA levels.
  • Distinct mechanisms (transcription vs. mRNA stability) were observed with different AKT inhibitors.

Purpose of the Study:

  • To investigate the role of AKT in regulating LDLR mRNA expression.
  • To examine the effects of five additional AKT inhibitors on LDLR mRNA levels.
  • To determine the involvement of specific AKT isoforms (AKT1, AKT2) in LDLR gene regulation.

Main Methods:

  • Treatment of HepG2 cells with various AKT inhibitors (ARQ-092, AKT inhibitor VIII, perifosine, AT7867, CCT128930).
  • Measurement of LDLR mRNA levels and LDLR promoter activity.
  • siRNA-mediated knockdown of AKT1 and AKT2 to assess isoform-specific effects on LDLR mRNA stability and promoter activity.

Main Results:

  • All five tested AKT inhibitors increased LDLR mRNA levels by inducing LDLR promoter activity.
  • CCT128930 demonstrated an additional effect by increasing LDLR mRNA stability.
  • Knockdown of either AKT1 or AKT2 upregulated LDLR promoter activity; only AKT2 knockdown stabilized LDLR mRNA.

Conclusions:

  • These findings provide strong evidence for AKT's involvement in regulating LDLR mRNA expression.
  • The results suggest AKT isoform specificity in the upregulation of LDLR mRNA.
  • AKT signaling pathways differentially impact LDLR gene transcription and mRNA stability.

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