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

• DOI: 10.1038/srep09023
• Publication Date: 2015-03-17T10:49:23Z
• Authors: R. Stöhr; M. Mavilio; A. Marino; V. Casagrande; B. Kappel; J. Möllmann; R. Menghini; G. Melino; M. Federici
• Keywords: Steatosis; Hyperlipidemia; Apolipoprotein E

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