Details

Autor(en) / Beteiligte

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

Titel

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

Ist Teil von

• Cell chemical biology, 2021-02, Vol.28 (2), p.169-179.e7

Ort / Verlag

Elsevier Ltd

Erscheinungsjahr

2021

Quelle

Alma/SFX Local Collection

Beschreibungen/Notizen

• 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. [Display omitted] •Dipyridamole, a PDE inhibitor, decreases lipogenesis by inhibiting SREBP maturation•Dipyridamole blocks SREBP independent of its PDE inhibitory action•A clickable photoprobe dipyridamole derivative binds to INSIG and SCAP•Dipyridamole derivatives are potentially therapeutic for lipid disorders Esquejo et al. report that dipyridamole, an FDA-approved anti-thrombotic phosphodiesterase (PDE) inhibitor, impedes endoplasmic reticulum to Golgi trafficking of sterol regulatory element-binding proteins (SREBPs) preventing their activation. A chemically modified version of dipyridamole that has no effect on PDE remains effective at SREBP blockage.