Oral Presentation Australian Diabetes Society and the Australian Diabetes Educators Association Annual Scientific Meeting 2014

Transgenic expression of dominant-active IDOL in liver: A novel  mouse model of hypercholesterolaemia and atherosclerosis    (#81)

Anna C Calkin 1 2 , Stephen D Lee 2 , Benjamin T Goult 3 , Jason Kim 2 , Caroline Van Stijn 2 , Li Zhang 2 , Louise Fairall 3 , Cynthia Hong 2 , John WR Schwabe 3 , Rajendra Tangirala 2 , Aldons J Lusis 2 , Peter Tontonoz 2
  1. Diabetes & Dyslipidaemia Group, Baker IDI Heart & Diabetes Institute, Melbourne, VIC, Australia
  2. University of California Los Angeles (UCLA), Los Angeles, CA, USA
  3. University of Leicester, Leicester, UK

Individuals with diabetes are 3-4 times more likely to develop cardiovascular disease. The excess lipids seen in the setting of diabetes can be deposited in tissues such as the blood vessels where they can promote atherosclerosis. Thus, the investigation of novel pathways involved in this process are required to identify new therapeutic targets to treat diabetes-associated vascular disease. Common models to study diabetes-associated atherosclerosis include the streptozocin (STZ)-diabetic LDLR KO or ApoE KO models. However, complicated breeding strategies arise when trying to test the effect of a transgene or knockout allele on these backgrounds, which is both time consuming and costly. Herein, we describe a novel mouse model of atherosclerosis based on single transgene hepatic expression of a dominant-active form of Inducible Degrader of the LDL receptor (IDOL). IDOL is an E3 ligase that regulates LDL receptor (LDLR)-dependent cholesterol uptake1, and we have identified a non-synonymous SNP encoding a functional variant within IDOL that is associated with increased plasma cholesterol in humans2.  We have demonstrated that IDOL controls its own stability through autoubiquitination of lysine residues within its unique FERM subdomain3. Mutation of these residues generates a degradation-resistant, dominant-active form of IDOL termed “super IDOL” (sIDOL). sIDOL was expressed in C57Bl/6J mice from the liver-specific albumin promoter (L-sIDOL transgenics). L-sIDOL mice showed dramatic reductions in hepatic LDLR protein and increased plasma LDL cholesterol levels on both chow and Western diets.  Moreover, L-sIDOL mice developed marked atherosclerotic lesions on a Western diet, which was more robust than has been reported for other transgenic models such as ApoE*3 Leiden mice, and did not require the addition of cholate to the diet.  Western diet-fed L-sIDOL mice exhibited elevated expression of LXR target genes and pro-inflammatory genes in their aortas. Future studies will investigate the effect of streptozotocin-induced diabetes in this model.