Abstract 12151: Hepatic Overexpression of Idol Reduces Ldl Catabolism by Targeting Ldl Receptor to Proteasomal Degradation in Mice and Hamsters
Inducible degrader of the LDL receptor (LDLR) (Idol), an E3 ubiquitin ligase for LDLR, reportedly targets LDLR to ubiquitin proteasome system (UPS), whereby increasing LDL levels in mice. However, previous studies were limited in animal models lacking CETP and in vivo LDL kinetics has not been performed. We therefore investigated the effects of liver-specific expression of Idol in both mice and hamsters on plasma lipids, together with LDL kinetic experiments.
Firstly, we confirmed that injection of an adenoviral vector harboring wild type Idol (Ad-Idol-WT) induced a liver-specific reduction in LDLR expression and increased serum total cholesterol and triglyceride levels. The increased cholesterol levels were attributable to the increases in LDL and VLDL, but not HDL, as evident from fast protein liquid chromatography. Interestingly, serum PCSK9 levels were increased by hepatic Idol overexpression compared to control. Idol-WT protein levels in liver were very low, even when driven from an exogenous adenoviral vector. In contrast, Idol-WT was detected in the presence of proteasome inhibitors in vitro, and Idol with Cys387Ala mutation in the catalytic RING domain was detected suggesting that Idol might catalyze its own degradation in UPS. Indeed, Ad-Idol-Cys387Ala transduction had no effect on LDLR expression and lipids levels. Kinetic analysis using 125I-labeled LDL revealed that Idol delayed LDL clearance as compared to control virus. 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 liver-specific expression of Idol attenuates LDLR expression then reduces LDL catabolism, thus resulting in the accumulation of LDL and VLDL. Further, these effects were independent of the presence or absence of CETP.
- © 2011 by American Heart Association, Inc.