2. Academic Validation
  3. Idol Depletion Protects against Spontaneous Atherosclerosis in a Hamster Model of Familial Hypercholesterolemia

Idol Depletion Protects against Spontaneous Atherosclerosis in a Hamster Model of Familial Hypercholesterolemia

  • Oxid Med Cell Longev. 2022 May 24;2022:1889632. doi: 10.1155/2022/1889632.
Chenxi Liang  # 1,  Xiaowei Wang  # 1 2,  Kenan Peng 1,  Pingping Lai 3,  Ziwei Liu 1,  Jiaao Ma 1,  Xin Chen 1,  Gang Liu 4,  Mingqi Zheng 4,  Yuhui Wang 3,  Hongyuan Yang 5,  George Liu 3,  Xunde Xian 3 6,  Mingming Gao 1 2
Affiliations

Affiliations

  • 1 Laboratory of Lipid Metabolism, Institute of Basic Medicine; Department of Biochemistry and Molecular Biology, College of Basic Medicine, Key Laboratory of Medical Biotechnology of Hebei Province, Cardiovascular Medical Science Center, Hebei Medical University, Shijiazhuang, Hebei 050017, China.
  • 2 The Key Laboratory of Neural and Vascular Biology, Ministry of Education, Shijiazhuang, Hebei 050017, China.
  • 3 Institute of Cardiovascular Sciences and Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, School of Basic Medical Sciences, Peking University, Beijing, China.
  • 4 Department of Cardiology, First Hospital of Hebei Medical University, Shijiazhuang, Hebei 050031, China.
  • 5 School of Biotechnology and Biomolecular Sciences, The University of New South Wales, Sydney, NSW 2052, Australia.
  • 6 Beijing Key Laboratory of Cardiovascular Receptors Research, Peking University Third Hospital, Beijing 100191, China.
  • # Contributed equally.
PMID: 35656026 DOI: 10.1155/2022/1889632
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.

Figures
Products