title: Stable liver-specific expression of human IDOL in humanized mice raises plasma cholesterol.
abstract: OBJECTIVE
  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.
  
  
  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 ∼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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Genetics, Division of Translational Medicine and Human Genetics of the Department of Medicine, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA salam.brahim@gmail.com.
authors.forename: Salam
authors.initials: S
authors.lastname: Ibrahim
authors.affiliation: Gene Therapy Program, Department of Pathology and Laboratory Medicine, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA.
authors.forename: Suryanarayan
authors.initials: S
authors.lastname: Somanathan
authors.affiliation: Department of Genetics, Division of Translational Medicine and Human Genetics of the Department of Medicine, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Billheimer
authors.affiliation: Gene Therapy Program, Department of Pathology and Laboratory Medicine, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA.
authors.forename: James M
authors.initials: JM
authors.lastname: Wilson
authors.affiliation: Department of Genetics, Division of Translational Medicine and Human Genetics of the Department of Medicine, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Rader
mesh_terms: D000818:Animals; D008078:Cholesterol, LDL / Q000378:metabolism; D006801:Humans; D006937:Hypercholesterolemia / Q000235:genetics*; D008099:Liver / Q000378:metabolism* / Q000821:virology; D051379:Mice; D018345:Mice, Knockout; D011973:Receptors, LDL / Q000235:genetics*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D054875:Ubiquitination / Q000235:genetics
chemical_list: D008078:Cholesterol, LDL; D011973:Receptors, LDL; C403126:MYLIP protein, human; C542022:Mylip protein, mouse; D044767:Ubiquitin-Protein Ligases
keywords: Hypercholesterolaemia; IDOL; LDLR; Lipoproteins; Therapeutic targets