ITCH modulates SIRT6 and SREBP2 to influence lipid metabolism and atherosclerosis in ApoE null mice

Scientific Reports
R StöhrMassimo Federici

Abstract

Atherosclerosis is a chronic inflammatory disease characterized by the infiltration of pro-inflammatory macrophages into a lipid-laden plaque. ITCH is an E3 ubiquitin ligase that has been shown to polarize macrophages to an anti-inflammatory phenotype. We therefore investigated the effect of ITCH deficiency on the development of atherosclerosis. ApoE-/-ITCH-/- mice fed a western diet for 12 weeks showed increased circulating M2 macrophages together with a reduction in plaque formation. Bone marrow transplantation recreated the haemopoietic phenotype of increased circulating M2 macrophages but failed to affect plaque development. Intriguingly, the loss of ITCH lead to a reduction in circulating cholesterol levels through interference with nuclear SREBP2 clearance. This resulted in increased LDL reuptake through upregulation of LDL receptor expression. Furthermore, ApoE-/-ITCH-/- mice exhibit reduced hepatic steatosis, increased mitochondrial oxidative capacity and an increased reliance on fatty acids as energy source. We found that ITCH ubiquitinates SIRT6, leading to its breakdown, and thus promoting hepatic lipid infiltration through reduced fatty acid oxidation. The E3 Ubiquitin Ligase ITCH modulates lipid metabolism impactin...Continue Reading

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Citations

Feb 9, 2016·Biochemistry·Nathaniel C NoyesDudley K Strickland
Jan 1, 2016·Carcinogenesis·Batia LerrerHaim Y Cohen
Dec 13, 2016·The Journal of Immunology : Official Journal of the American Association of Immunologists·Tristan GalbasJacques Thibodeau
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Feb 23, 2019·G3 : Genes - Genomes - Genetics·Mohammad Reza Bakhtiarizadeh, Seyed Alireza Salami
Mar 7, 2020·Current Medicinal Chemistry·Zhi-Xiang ZhouZhi-Sheng Jiang

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Datasets Mentioned

BETA
AF3985

Methods Mentioned

BETA
FACS
PCR
ubiquitination
Assay
transfection
immunoprecipitation

Software Mentioned

GraphPAD Prism

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