Stable liver-specific expression of human IDOL in humanized mice raises plasma cholesterol

Cardiovascular Research
Salam IbrahimDaniel Rader

Abstract

IDOL (inducible degrader of the low-density lipoprotein receptor, LDLR) is an E3 ubiquitin ligase that promotes the ubiquitination and degradation of the LDLR. IDOL is a potential therapeutic target for the development of a novel class of low-density lipoprotein cholesterol (LDL-C)-lowering therapies. In an attempt to develop a mouse model for testing IDOL inhibitors, we examined the effects of adeno-associated virus (AAV)-mediated stable expression of human IDOL in the livers of mice 'humanized' with regard to lipoprotein metabolism. Using a liver-specific AAV serotype 8 (AAV8)-mediated delivery, AAV-hIDOL produced a dose-dependent increase in LDL-C levels and a decrease in liver LDLR protein. Furthermore, we expressed hIDOL in a 'humanized' mouse model of heterozygous familial hypercholesterolaemia (LDLR(+/-)/Apobec1(-/-)/hApoB-Tg, LAhB). In this model, total cholesterol (TC) and LDL-C levels were increased by ∼60% starting from 1 week and were sustainable for at least 3 weeks post-injection. Finally, we demonstrate that the effects caused by hIDOL expression are LDLR- dependent given the unchanged plasma lipids in LAhB mice lacking LDLR. In conclusion, our study demonstrates a dose-dependent physiological effect of human IDO...Continue Reading

References

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Citations

Jul 28, 2018·Frontiers in Pharmacology·Maria MytilinaiouHarpal S Randeva
Oct 11, 2019·Arteriosclerosis, Thrombosis, and Vascular Biology·Dilare AdiJie Luo
Nov 21, 2017·The American Journal of Pathology·Karin E BornfeldtJenny E Kanter

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