title: ITCH modulates SIRT6 and SREBP2 to influence lipid metabolism and atherosclerosis in ApoE null mice.
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 impacting on atherosclerosis progression independently from effects on myeloid cells polarization through control of SIRT6 and SREBP2 ubiquitination. Thus, modulation of ITCH may provide a target for the treatment of hypercholesterolemia and hyperlipidemia.
authors.affiliation: Department of Systems Medicine University of Rome "Tor Vergata"
authors.forename: R
authors.initials: R
authors.lastname: Stöhr
authors.affiliation: Department of Systems Medicine University of Rome "Tor Vergata"
authors.forename: M
authors.initials: M
authors.lastname: Mavilio
authors.affiliation: Department of Systems Medicine University of Rome "Tor Vergata"
authors.forename: A
authors.initials: A
authors.lastname: Marino
authors.affiliation: Department of Systems Medicine University of Rome "Tor Vergata"
authors.forename: V
authors.initials: V
authors.lastname: Casagrande
authors.affiliation: Department of Systems Medicine University of Rome "Tor Vergata"
authors.forename: B
authors.initials: B
authors.lastname: Kappel
authors.affiliation: Medizinische Klinik I, University Hospital Aachen.
authors.forename: J
authors.initials: J
authors.lastname: Möllmann
authors.affiliation: Department of Systems Medicine University of Rome "Tor Vergata"
authors.forename: R
authors.initials: R
authors.lastname: Menghini
authors.affiliation: 1] Department of Experimental Medicine and Surgery University of Rome "Tor Vergata" [2] Medical Research Council, Toxicology Unit, Leicester LE1 9HN UK.
authors.forename: G
authors.initials: G
authors.lastname: Melino
authors.affiliation: 1] Department of Systems Medicine University of Rome "Tor Vergata" [2] Center for Atherosclerosis, University Hospital "Policlinico Tor Vergata", Rome.
authors.forename: M
authors.initials: M
authors.lastname: Federici
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency*; D050197:Atherosclerosis / Q000235:genetics* / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D016026:Bone Marrow Transplantation; D002784:Cholesterol / Q000097:blood / Q000378:metabolism; D004195:Disease Models, Animal; D005234:Fatty Liver / Q000378:metabolism / Q000473:pathology; D007249:Inflammation / Q000235:genetics / Q000378:metabolism; D050356:Lipid Metabolism; D008099:Liver / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism; D010084:Oxidation-Reduction; D037761:Sirtuins / Q000378:metabolism*; D051782:Sterol Regulatory Element Binding Protein 2 / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D001057:Apolipoproteins E; D051782:Sterol Regulatory Element Binding Protein 2; D002784:Cholesterol; C471637:Itch protein, mouse; D044767:Ubiquitin-Protein Ligases; C501860:Sirt6 protein, mouse; D037761:Sirtuins