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Idol Depletion Protects against Spontaneous Atherosclerosis in a Hamster Model of Familial Hypercholesterolemia
Abstract
Inducible degrader of low‐density lipoprotein (LDL) receptor (Idol) is an E3 ubiquitin ligase coded by Idol, the target gene of liver X receptor (LXR), which primarily mediates the ubiquitination and lysosomal degradation of low‐density lipoprotein receptor (LDLR). Previous studies from independent groups have shown that plasma cholesterol regulation by the LXR‐Idol‐LDLR axis is tissue‐ and species‐specific, indicating that the precise molecular mechanism by which Idol modulates lipid metabolism has not been completely understood and needs to be further validated in other species. Hamster, a small rodent animal model expressing endogenous cholesterol ester transfer protein (CETP), possesses many metabolic characteristics that are different from mouse but similar to human. In this study, an Idol knockout (Idol-/-) hamster model was developed using CRISPR/Cas9 gene editing system to investigate the effect of Idol depletion on plasma lipid metabolism and atherosclerosis. Our results showed that there were no significant differences in hepatic LDLR protein and plasma cholesterol levels in Idol-/- hamsters compared with wild‐type (WT) controls, which was consistent with the observation that LXR agonist treatment increased the expression of Idol mRNA in the small intestine but not in the liver of WT hamsters. However, we found that plasma triglyceride (TG) levels were significantly reduced in Idol-/- hamsters due to an enhancement of TG clearance. In addition, the morphological data demonstrated that inactivation of Idol significantly lowered plasma total cholesterol and TG levels and protected against spontaneous atherosclerotic lesions in aged LDLR knockout hamsters on a chow diet but had no effect on diet‐induced atherosclerosis in hamsters lacking one copy of the Ldlr gene. In conclusion, our findings suggest that Idol can regulate plasma lipid metabolism and atherosclerosis independent of LDLR function.
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Absence of Idol in hamsters did not alter hepatic LDLR abundance or plasma cholesterol levels, but resulted in significantly reduced plasma triglycerides and protection from development of atherosclerosis.
“Absence of Idol in hamsters did not alter hepatic LDLR abundance or plasma cholesterol levels.However, this resulted in significantly reduced plasma triglycerides and protection from development of atherosclerosis [77].”
From The low-density lipoprotein receptor: Emerging post-transcriptional regulatory mechanisms (2025) · cites this paper as [77]
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Bligh, E. G., & Dyer, W. J. (1959) · Canadian Journal of Biochemistry and Physiology · doi:10.1139/o59-099 · Cited by 54,751 · cited 1×
“The lipids were extracted according to the improved method of Bligh and Dyer [18].”
The LXR–Idol Axis Differentially Regulates Plasma LDL Levels in Primates and Mice
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The low-density lipoprotein receptor: Emerging post-transcriptional regulatory mechanisms
Ndoj, K., Meurs, A., Papaioannou, D., Bjune, K., & Zelcer, N. (2025) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2024.119082 · Cited by 17
Metadata
- Authors
- Liang, C., Wang, X., Peng, K., Lai, P., Liu, Z., Ma, J., Chen, X., Liu, G., Zheng, M., Wang, Y., Yang, H., Liu, G., Xian, X., & Gao, M.
- Venue
- Oxidative Medicine and Cellular Longevity
- Publisher
- Wiley
- Published
- 2022-01
- Volume
- 2022
- Issue
- 1
- ISSN
- 1942-0900
- 1942-0994
- PMC
- PMC9155911
- Cited by
- 8
- References
- 5
- Language
- en
- Funders
- Natural Science Foundation of Hebei Province (H2021206399, H2019206715)
- National Natural Science Foundation of China (82070460, 31771306, 81700386)
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