The HDL receptor, scavenger receptor class B type I (SR-BI), is expressed on the surface of multiple cell types and has been shown to mediate both HDL-dependent atheroprotective © 2014 American Heart Association, Inc.Arterioscler Thromb Vasc Biol is available at http://atvb.ahajournals.org DOI: 10.1161/ATVBAHA.114.304200Objective-Deficiency of the high-density lipoprotein receptor, scavenger receptor class B, type I (SR-BI), in apolipoprotein E knockout or hypomorphic mice, respectively, results in spontaneous or diet-inducible occlusive coronary artery (CA) atherosclerosis, myocardial infarction, and early death. Here, we examine effects of SR-BI deficiency on cardiovascular phenotypes in low-density lipoprotein receptor (LDLR) knockout mice fed different atherogenic diets. Approach and Results-SR-BI/LDLR double knockout and control LDLR knockout mice were fed atherogenic diets containing different amounts of fat, cholesterol, and sodium cholate. Double knockout mice fed atherogenic diets high in cholesterol exhibited significantly reduced survival compared with LDLR knockout mice fed the same diets. In addition to increased diet-accelerated aortic sinus atherosclerosis, we observed significant diet-induced CA atherosclerosis in double knockout mice and diet-dependent accumulation of platelets in CA atherosclerotic plaques. This was accompanied by substantial myocardial fibrosis in double knockout mice fed high cholesterol diets. Atherogenic diet fed double knockout mice also exhibited higher circulating cytokine levels, monocytosis with increased proportions of Ly6C hi and Ly6C int monocytes, and higher adhesion molecule expression in CA endothelial cells compared with control LDLR knockout mice. Conclusions-Diet-accelerated atherosclerosis and occlusive, platelet-rich CA disease in SR-BI/LDLR double knockout mice is affected by amounts of cholesterol and cholate in atherogenic diets and is accompanied by increased expression of vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 in CAs and increased Ly6C hi and Ly6C Fuller et al Coronary Atherosclerosis in SR-BI/LDLR dKO Mice 2395signaling 8,9 and selective lipid transfer between HDL and cells, which is critical for functional reverse cholesterol transport, the major avenue for cholesterol removal from peripheral tissues.8,10 Deficiency of SR-BI not only accelerates atherosclerosis in the aortic sinus of apoE knockout mice 11 but also renders these mice susceptible to spontaneous occlusive CA atherosclerosis, myocardial infarction, and ultimately early death. 12 A related model, the SR-BI knockout/apoE hypomorphic mouse, develops a similar phenotype when fed high fat, high cholesterol (HFC) diets. 13,14 We have previously shown that SR-BI deficiency increases atherosclerosis in the aortas of LDLR knockout mice fed a high-fat (HF) Western-type diet; however, reduced survival was not observed in these mice, and CA atherosclerosis was not assessed. 15In the current study, we tested the effects of feeding SR-BI/ LDLR double knockout (dKO) mic...

This review discusses the progress and challenges in tetratricopeptide repeat domain 7A deficiency, a monogenic cause of severe intestinal disease and immunodeficiency. Patient reports and functional studies to date are amalgamated into graphic summaries, highlighting patient mutations and the known role of tetratricopeptide repeat domain 7A in the cell.

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Very early onset inflammatory bowel disease (VEOIBD) denotes children with onset of IBD before six years of age. A number of monogenic disorders are associated with VEOIBD including tetratricopeptide repeat domain 7A (TTC7A) deficiency. TTC7A-deficiency is characterized by apoptotic colitis in milder cases with severe intestinal atresia and immunodeficiency in cases with complete loss of protein. We used whole exome sequencing in a VEOIBD patient presenting with colitis characterized by colonic apoptosis and no identified known VEOIBD variants, to identify compound heterozygous deleterious variants in the Ubiquitin protein ligase E3 component N-recognin 5 (UBR5) gene. Functional studies demonstrated that UBR5 co-immunoprecipitates with the TTC7A and the UBR5 variants had reduced interaction between UBR5 and TTC7A. Together this implicates UBR5 in regulating TTC7A signaling in VEOIBD patients with apoptotic colitis.

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