The 5'-AMP-Activated Protein Kinase Regulates the Function and Expression of Human Organic Anion Transporting Polypeptide 1A2

Mol Pharmacol. 2018 Dec;94(6):1412-1420. doi: 10.1124/mol.118.113423. Epub 2018 Oct 22.


The organic anion transporting polypeptides (OATPs) are important membrane proteins that mediate the cellular uptake of drugs and endogenous substances. OATP1A2 is widely distributed in many human tissues that are targeted in drug therapy; defective OATP1A2 leads to altered drug disposition influencing therapeutic outcomes. 5'-AMP-activated protein kinase (AMPK) signaling plays an important role in the pathogenesis of the metabolic syndrome characterized by an increased incidence of type II diabetes and nonalcoholic fatty liver disease. This study investigated the regulatory role of AMPK in OATP1A2 transport function and expression. We found that the treatment of AMPK-specific inhibitor compound C (dorsomorphin dihydrochloride) decreased OATP1A2-mediated uptake of estrone-3-sulfate in a concentration- and time-dependent manner. The impaired OATP1A2 function was associated with a reduced Vmax [154.6 ± 17.9 pmol × (μg × 4 minutes)-1 in compound C-treated cells vs. 413.6 ± 52.5 pmol × (μg × 4 minutes)-1 in controls]; the Km was unchanged. The cell-surface expression of OATP1A2 was decreased by compound C treatment, but total cellular expression was unchanged. The impaired cell-surface expression of OATP1A2 was associated with accelerated internalization and impaired targeting/recycling. Silencing of the AMPK α1-subunit using specific small interfering RNA corroborated the findings with compound C and revealed a role for AMPK in regulating OATP1A2 protein stability. Overall, this study implicated AMPK in the regulation of the function and expression of OATP1A2, which potentially impacts on the disposition of OATP1A2 drug substrates that may be used to treat patients with the metabolic syndrome and other diseases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinases / metabolism*
  • Biological Transport / drug effects
  • Cell Line
  • Diabetes Mellitus, Type 2 / metabolism
  • Estrone / analogs & derivatives
  • Estrone / pharmacology
  • HEK293 Cells
  • Humans
  • Organic Anion Transporters / metabolism*
  • Protein Stability / drug effects
  • Signal Transduction / drug effects
  • Signal Transduction / physiology


  • Organic Anion Transporters
  • SLCO1A2 protein, human
  • Estrone
  • AMP-Activated Protein Kinases
  • estrone sulfate