Dipyridamole Inhibits Lipogenic Gene Expression by Retaining SCAP-SREBP in the Endoplasmic Reticulum

Ryan M. Esquejo, Manuel Roqueta-Rivera, Wei Shao, Peter E. Phelan, Uthpala Seneviratne, Christopher W. am Ende, Paul M. Hershberger, Carolyn E. Machamer, Peter J. Espenshade, Timothy F. Osborne

Research output: Contribution to journalArticlepeer-review


Sterol regulatory element-binding proteins (SREBPs) are master transcriptional regulators of the mevalonate pathway and lipid metabolism and represent an attractive therapeutic target for lipid metabolic disorders. SREBPs are maintained in the endoplasmic reticulum (ER) in a tripartite complex with SREBP cleavage-activating protein (SCAP) and insulin-induced gene protein (INSIG). When new lipid synthesis is required, the SCAP-SREBP complex dissociates from INSIG and undergoes ER-to-Golgi transport where the N-terminal transcription factor domain is released by proteolysis. The mature transcription factor translocates to the nucleus and stimulates expression of the SREBP gene program. Previous studies showed that dipyridamole, a clinically prescribed phosphodiesterase (PDE) inhibitor, potentiated statin-induced tumor growth inhibition. Dipyridamole limited nuclear accumulation of SREBP, but the mechanism was not well resolved. In this study, we show that dipyridamole selectively blocks ER-to-Golgi movement of the SCAP-SREBP complex and that this is independent of its PDE inhibitory activity.

Original languageEnglish (US)
Pages (from-to)169-179.e7
JournalCell Chemical Biology
Issue number2
StatePublished - Feb 18 2021


  • Insig
  • SCAP inhibitor
  • cancer
  • cholesterol
  • gene expression
  • lipogenesis
  • obesity
  • repurposing dipyridamole
  • triglycerides

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmacology
  • Drug Discovery
  • Clinical Biochemistry


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