Transgenic Expression of Dominant-Active IDOL in Liver Causes Diet-Induced Hypercholesterolemia and Atherosclerosis in Mice
Rationale: The E3 ubiquitin ligase IDOL triggers lysosomal degradation of the LDL receptor. The tissue-specific effects of the IDOL pathway on plasma cholesterol and atherosclerosis have not been examined.
Objective: Given that the liver is the primary determinant of plasma cholesterol levels, we sought to examine the consequence of effect of chronic liver-specific expression of a dominant active form of IDOL in mice.
Methods and Results: We expressed a degradation-resistant, dominant-active form of IDOL (sIDOL) in C57Bl/6J mice from the liver-specific albumin promoter (L-sIDOL transgenics). L-sIDOL mice were fed a Western diet for 20 or 30 weeks and then analyzed for plasma lipid levels and atherosclerotic lesion formation. 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 when fed a Western diet. Lesion formation in L-sIDOL mice was more robust than in ApoE*3 Leiden mice and did not require the addition of cholate to the diet. Western diet-fed L-sIDOL mice had elevated expression of LXR target genes and pro-inflammatory genes in their aortas.
Conclusions: Liver-specific expression of dominant-active IDOL is associated with hypercholesterolemia and a marked elevation in atherosclerotic lesions. Our results show that increased activity of the IDOL pathway in the liver can override other LDLR regulatory pathways leading to cardiovascular disease. L-sIDOL mice are a robust, dominantly-inherited, diet-inducible model for the study of atherosclerosis.
- Received May 22, 2014.
- Revision received June 12, 2014.
- Accepted June 16, 2014.