| First Author | Ibrahim S | Year | 2016 |
| Journal | Cardiovasc Res | Volume | 110 |
| Issue | 1 | Pages | 23-9 |
| PubMed ID | 26786161 | Mgi Jnum | J:252573 |
| Mgi Id | MGI:6107371 | Doi | 10.1093/cvr/cvw010 |
| Citation | Ibrahim S, et al. (2016) Stable liver-specific expression of human IDOL in humanized mice raises plasma cholesterol. Cardiovasc Res 110(1):23-9 |
| abstractText | AIMS: 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. METHODS AND RESULTS: 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 approximately 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. CONCLUSION: In conclusion, our study demonstrates a dose-dependent physiological effect of human IDOL on LDL metabolism in mice. This provides a potential model for preclinical testing of IDOL inhibitors for reduction of LDL-C levels. |
