Abstract 16185: CETP Inhibitor Anacetrapib Downregulates Both LDL Receptor and PCSK9 Expression in Cultured Liver Cells Through a SREBP Dependent Mechanism
Authors: Bin Dong, Amar B. Singh, Chin Fung Kelvin Kan, Jingwen Liu
Journal: Circulation (2013)

Abstracts and presentations are embargoed for release at date and time ofpresentation or time of AHA/ASA news event. Information may not be releasedbefore then. Failure to honor embargo policies will result in the abstract beingwithdrawn and barred from presentation. Core 2. Epidemiology and Prevention of CV Disease: Physiology,Pharmacology and Lifestyle Session Title: New Insights into Lipoprotein Metabolism Abstract 16185: CETP Inhibitor AnacetrapibDownregulates Both LDL Receptor and PCSK9Expression in Cultured Liver Cells Through aSREBP Dependent Mechanism Bin Dong; Amar B Singh; Chin Fung Kelvin Kan; Jingwen Liu Rsch Service, Palo Alto VA Health Care System, Palo Alto, CA The plasma protein cholesteryl ester transfer protein (CETP) mediates theexchange of cholesteryl esters (CE) and TG between HDL and apoB-containinglipoprotein particles. Thus, inhibition of CETP activity raises plasma HDL-C andlowers LDL-C. Anacetrapid (ANA) and dalcetrapid (DAL) are potent CETP inhibitorsand their effects on raising plasma HDL-C are demonstrated in clinical trials.Particularly, ANA monotherapy increases HDL-C by over 100% and lowers LDL-Cby 30-40% in dyslipidemic patients. Besides CETP, PCSK9 is another promisingtherapeutic target. Plasma PCSK9 binds to hepatic LDL receptor (LDLR), promotingits degradation, and consequently raising plasma LDL-C. It was recently reportedthat CETP inhibitors (ANA, DAL, and K-312) exhibited negative effects on PCSK9expression in HepG2 cells, which could be potentially a causal factor for LDL-Creduction observed in humans, additional to CETP activity inhibition. The currentstudy aimed to evaluate the direct effects of ANA and DAL on LDLR and PCSK9expression in cultured hepatic cells and to further elucidate the underlyingmechanism. Unexpectedly, we found that ANA treatment of HepG2 cellssignificantly reduced protein levels of PCSK9 and LDLR to 70% and 50% of controlat 1 μM and 10 μM concentrations, while DAL up to 10 μM had no effect. Wefurther examined the effects of ANA on human primary hepatocytes. The datagenerated from 3 independent donors showed 41% reduction of LDLR protein(p<0.01) and 27% reduction in PCSK9 protein levels (p<0.05) by 3 μM ANA after24 h treatment. The inhibitory action of ANA on LDLR/PCSK9 was furtherdemonstrated in mouse primary hepatocytes and mouse hepatoma cell lines,thereby suggesting an action independent of CETP protein. Q-PCR analysis showeda similar degree of decrease in LDLR/PCSK9 mRNA levels by ANA comparable to itseffects on their respective proteins. LDLR and PCSK9 promoter analyses furthersuggested that ANA inhibits LDLR/PCSK9 expression at the level of transcription.Finally, we observed that treating HepG2 cells with ANA reduced the amount ofmature SREBP2, the common trans-activator of LDLR and PCSK9. In summary,these novel findings suggest that ANA most likely affects SREBP2 processing whichleads to attenuated transcriptions of LDLR and PCSK9.Author Disclosures: B. Dong: None. A.B. Singh: None. C. Kan: None. J. Liu: None.Key Words: CETP inhibitors • Gene expression • Drugs • Lipoproteins • HDLelevating therapies