Circulation Research RES Transgenic Expression of Dominant-Active IDOL in Liver Causes Diet-Induced Hypercholesterolemia and Atherosclerosis in Mice Liver IDOL Expression Induces Atherosclerosis CIRCRES/2014/304440D CIRCRES/2014/304440D 10.1161/CIRCRESAHA.115.304440 115 08/01/14 4 Bridges-Lyman Gemma 410-3275005 410-3279322 Tall, Alan Columbia University Dr. Peter Tontonoz ptontonoz@mednet.ucla.edu Dr. University of California, Los Angeles Howard Hughes Medical Institute, Department of Pathology and Laboratory Medicine, University of California, Los Angeles, MacDonald Research Laboratories 5-748, 675 Charles E. Young Drive Sout Los Angeles California 90095-1662 UNITED STATES 310-206-4546 310-267-0382 3076 Anna C Calkin Baker IDI Anna.Calkin@bakeridi.edu.au 163925 Stephen D Lee University of California, Los Angeles sdlee@mednet.ucla.edu 163926 Jason Kim University of California, Los Angeles jasonkim@mednet.ucla.edu 122091 Caroline M.W. van Stijn University of California, Los Angeles caroline_vanstijn@hotmail.com 188259 Cynthia Hong University of California, Los Angeles hongc@seas.ucla.edu 104313 Xiao-hui Wu University of California, Los Angeles xiaohuiwu@ucla.edu 216617 Aldons J Lusis University of California, Los Angeles jlusis@mednet.ucla.edu 1322 Rajendra K. Tangirala University of California, Los Angeles rtangirala@mednet.ucla.edu 11075 Peter Tontonoz University of California, Los Angeles ptontonoz@mednet.ucla.edu 3076 05/22/2014 05/22/2014 06/12/2014 06/16/2014 06/16/2014 Regular Article Vascular Biology E3 ubiquitin ligase LDL cholesterol mouse model CIRCRES/2013/302584 Transgenic expression of dominant-active IDOL in liver causes diet-induced hypercholesterolemia and atherosclerosis in mice <p><i><b><u>Rationale:</u></b></i> The E3 ubiquitin ligase IDOL triggers lysosomal degradation of the LDL receptor. The tissue-specific effects of the IDOL pathway on plasma cholesterol and atherosclerosis have not been examined. </p><p><i><b><u>Objective:</u></b></i> Given that the liver is the primary determinant of plasma cholesterol levels, we sought to examine the consequence of effect of chronic liver-specific expression of a dominant active form of IDOL in mice. </p><p><i><b><u>Methods and Results:</u></b></i> We expressed a degradation-resistant, dominant-active form of IDOL (sIDOL) in C57Bl/6J mice from the liver-specific albumin promoter (L-sIDOL transgenics). L-sIDOL mice were fed a Western diet for 20 or 30 weeks and then analyzed for plasma lipid levels and atherosclerotic lesion formation. L-sIDOL mice showed dramatic reductions in hepatic LDLR protein and increased plasma LDL cholesterol levels on both chow and Western diets. Moreover, L-sIDOL mice developed marked atherosclerotic lesions when fed a Western diet. Lesion formation in L-sIDOL mice was more robust than in ApoE*3 Leiden mice and did not require the addition of cholate to the diet. Western diet-fed L-sIDOL mice had elevated expression of LXR target genes and pro-inflammatory genes in their aortas. </p><p><i><b><u>Conclusions:</u></b></i> Liver-specific expression of dominant-active IDOL is associated with hypercholesterolemia and a marked elevation in atherosclerotic lesions. Our results show that increased activity of the IDOL pathway in the liver can override other LDLR regulatory pathways leading to cardiovascular disease. L-sIDOL mice are a robust, dominantly-inherited, diet-inducible model for the study of atherosclerosis. </p> 1 2 2 3 7 yes CircRes_CIRCRES-2014-304440D.xml CircRes_CIRCRES-2014-304440D_file1.docx CircRes_CIRCRES-2014-304440D_supp1.pdf

CircRes_CIRCRES-2014-304440D_fig1_BW.pptx

CircRes_CIRCRES-2014-304440D_fig2_BW.pptx

CircRes_CIRCRES-2014-304440D_fig3_BW.pptx

CircRes_CIRCRES-2014-304440D_fig4_4C.pptx

CircRes_CIRCRES-2014-304440D_fig5_4C.pptx

CircRes_CIRCRES-2014-304440D_fig6_BW.pptx

CircRes_CIRCRES-2014-304440D_fig7_4C.pptx

CircRes_CIRCRES-2014-304440D_merge.pdf CircRes_CIRCRES-2014-304440D_Tangirala_11075_disclosure.pdf CircRes_CIRCRES-2014-304440D_Tangirala_11075_copyright.pdf CircRes_CIRCRES-2014-304440D_Lusis_1322_disclosure.pdf CircRes_CIRCRES-2014-304440D_Lusis_1322_copyright.pdf CircRes_CIRCRES-2014-304440D_Lee_163926_disclosure.pdf CircRes_CIRCRES-2014-304440D_Lee_163926_copyright.pdf CircRes_CIRCRES-2014-304440D_van_Stijn_188259_disclosure.pdf CircRes_CIRCRES-2014-304440D_van_Stijn_188259_copyright.pdf CircRes_CIRCRES-2014-304440D_Wu_216617_disclosure.pdf CircRes_CIRCRES-2014-304440D_Wu_216617_copyright.pdf CircRes_CIRCRES-2014-304440D_Hong_104313_disclosure.pdf CircRes_CIRCRES-2014-304440D_Hong_104313_copyright.pdf CircRes_CIRCRES-2014-304440D_Kim_122091_disclosure.pdf CircRes_CIRCRES-2014-304440D_Kim_122091_copyright.pdf CircRes_CIRCRES-2014-304440D_Tontonoz_3076_disclosure.pdf CircRes_CIRCRES-2014-304440D_Tontonoz_3076_copyright.pdf CircRes_CIRCRES-2014-304440D_Calkin_163925_disclosure.pdf CircRes_CIRCRES-2014-304440D_Calkin_163925_copyright.pdf PAP: 06/16/14 Funding: Howard Hughes Medical Institute (HHMI): Yes National Institutes of Health (NIH): Yes Not applicable for this manuscript: No Other: No Wellcome Trust: No Subject Codes: [130] Animal models of human disease [145] Genetically altered mice [90] Lipid and lipoprotein metabolism [96] Mechanism of atherosclerosis/growth factors gbridgeslyman