Abstract 12815: Hepatic Overexpression of Idol Accelerates LDL Receptor Degradation Partly by Increasing Circulating PCSK9 Levels via SREBP2/LDL Receptor-Dependent Pathways

Abstract

Inducible degrader of the LDLR (Idol), together with protein convertase subtilisin/kexin type 9 (PCSK9), modulates posttranslational degradation of LDL receptor (LDLR), whereby regulating circulating LDL levels. However, it remains unclear whether, if so how, these LDLR degraders interact each other. We therefore investigated effects of liver-specific expression of Idol on LDL/PCSK9 metabolism in mice and hamsters. Firstly, we confirmed that injection of an adenoviral vector harboring mouse Idol (Ad-mIdol) induced a liver-specific reduction in LDLR expression and increased VLDL/LDL cholesterol levels in wild type (WT) mice. Interestingly, hepatic Idol overexpression markedly increased plasma PCSK9 levels in WT mice (Figure A). In LDLR deficient (LDLR-/-) mice, plasma PCSK9 levels were already markedly elevated at baseline; levels comparable to those in Ad-mIdol-injected WT mice and Idol did not affect plasma PCSK9 levels compared to control, indicating that Idol increased circulating PCSK9 in an LDLR-dependent fashion. To further investigate molecular mechanism, we performed western blots and real-time RT-PCR analyses and found that Ad-mIdol enhanced hepatic PSCK9 expression, accompanying activation of sterol regulatory element-binding protein 2 (SREBP2) and increased expression of its target genes, including LDLR and SREBP2 itself. PSCK9/LDLR promoter analysis using HepG2 cells demonstrated that Idol transactivated PCSK9/LDLR in SREBP2/LDLR-dependent manners (Figure B), supporting in vivo data. Finally, we repeated above experiments in hamsters, CETP-expressing animal model, and obtained similar results.In conclusions, the present study demonstrates for the first time that hepatic Idol overexpression directly and indirectly accelerates LDLR degradation partly by increasing circulating PCSK9 levels via SREBP2/LDLR-dependent pathway.