Mechanisms
Exon-9-deleted CETP isoform blocks full-length CETP secretion and redirects cells toward storing triglyceride (J Lipid Res 2020)
Original title: Exon 9-deleted CETP inhibits full length-CETP synthesis and promotes cellular triglyceride storage
CETP exists as a full-length (FL) form and an exon-9-deleted (E9-deleted) isoform whose function has been unclear. Researchers found that coexpressing FL- and E9-deleted CETP in cells that naturally make CETP lowered cellular levels of both proteins by reducing their synthesis, with the predominant effect being impaired FL-CETP synthesis, since E9-deleted CETP is not itself secreted but forms a complex with FL-CETP. Overexpressing E9-deleted CETP alone stimulated triglyceride synthesis and doubled stored triglyceride in cells that naturally make CETP and in mouse cells that do not. In vitro, E9-deleted CETP promoted, less effectively than FL-CETP, the transfer of triglyceride from ER membranes to lipid droplets, and inhibited FL-CETP-driven transfer. The findings show the two CETP isoforms interact to mutually reduce their own levels and alter cellular triglyceride handling in contrary directions.
Original abstract
Cholesteryl ester transfer protein (CETP) exists as full-length (FL) and exon 9 (E9)-deleted isoforms. The function of E9-deleted CETP is poorly understood. Here, we investigated the role of E9-deleted CETP in regulating the secretion of FL-CETP by cells and explored its possible role in intracellular lipid metabolism. CETP overexpression in cells that naturally express CETP confirmed that E9-deleted CETP is not secreted, and showed that cellular FL- and E9-deleted CETP form an isolatable complex. Coexpression of CETP isoforms lowered cellular levels of both proteins and impaired FL-CETP secretion. These effects were due to reduced synthesis of both isoforms; however, the predominate consequence of FL- and E9-deleted CETP coexpression is impaired FL-CETP synthesis. We reported previously that reducing both CETP isoforms or overexpressing FL-CETP impairs cellular triglyceride (TG) storage. To investigate this further, E9-deleted CETP was expressed in SW872 cells that naturally synthesize CETP and in mouse 3T3-L1 cells that do not. E9-deleted CETP overexpression stimulated SW872 triglyceride synthesis and increased stored TG 2-fold. Expression of E9-deleted CETP in mouse 3T3-L1 cells produced a similar lipid phenotype. In vitro, FL-CETP promotes the transfer of TG from ER-enriched membranes to lipid droplets. E9-deleted CETP also promoted this transfer, although less effectively, and it inhibited the transfer driven by FL-CETP. We conclude that FL- and E9-deleted CETP isoforms interact to mutually decrease their intracellular levels and impair FL-CETP secretion by reducing CETP biosynthesis. E9-deleted CETP, like FL-CETP, alters cellular TG metabolism and storage but in a contrary manner.
Summary written by cetpinhibition.org from the published abstract; figures as published. Page updated 19 August 2026. Methods.