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Updated: Apr 28, 2026
A Familial Hypercholesterolemia Human Liver Chimeric Mouse Model Using Induced Pluripotent Stem Cell-derived Hepatocytes
Published on: September 15, 2018
Transgenic expression of dominant-active IDOL in liver causes diet-induced hypercholesterolemia and atherosclerosis
Anna C Calkin1, Stephen D Lee1, Jason Kim1
1From the Departments of Pathology and Laboratory Medicine (A.C.C., S.D.L., X.-H.W., C.H., P.T.), Department of Medicine, Division of Endocrinology (J.K., C.M.W.V.S., R.I.T.), Department of Medicine, Division of Cardiology (X.-H.W., A.J.L.), and Departments of Human Genetics and Microbiology Immunology and Molecular Genetics (A.J.L.), David Geffen School of Medicine, University of California, Los Angeles; Howard Hughes Medical Institute, Los Angeles, CA (A.C.C., S.D.L., C.H., P.T.); and Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia (A.C.C.).
Rationale:
The E3 ubiquitin ligase inducible degrader of the low-density lipoprotein receptor (IDOL) triggers lysosomal degradation of the low-density lipoprotein 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 (super 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 low-density lipoprotein receptor protein and increased plasma low-density lipoprotein 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 apolipoprotein E*3 Leiden mice and did not require the addition of cholate to the diet. Western diet-fed L-sIDOL mice had elevated expression of liver X receptor target genes and proinflammatory 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 low-density lipoprotein receptor regulatory pathways leading to cardiovascular disease. L-sIDOL mice are a robust, dominantly inherited, diet-inducible model for the study of atherosclerosis.
