Abstract 16404: CETP Inhibitor K-312 Lowers PCSK9 Expression and LDL Cholesterol Levels in vivo

Background: Despite potent LDL-cholesterol (LDL-C) therapies, substantial residual cardiovascular risk remains. Proprotein convertase subtilisin/kexin 9 (PCSK9) is a promising target for lowering LDL-C. We recently demonstrated that K-312, originally found as a cholesteryl ester transfer protein (CETP) inhibitor, decreased PCSK9 expression in vitro through the reduction of its promoter activity. The present study has further examined the underlying molecular mechanisms and in vivo effects of K-312 on PCSK9 levels using mass spectrometry. Methods and Results: CETP silencing by siRNA in the human hepatocyte cell line HepG2 did not compromise suppression of PCSK9 expression by K-312, indicating a mechanism independent of CETP inhibition. Transcription factors sterol-regulatory element binding protein (SREBP)-1 and SREBP-2 bind to the sterol regulatory element (SRE) of PCSK9 promoter when their precursor forms are cleaved into active forms. K-312 treatment decreased binding of SREBP-1 and SREBP-2 to SRE of th...