title: Transgenic expression of dominant-active IDOL in liver causes diet-induced hypercholesterolemia and atherosclerosis in mice.
abstract: BACKGROUND
  The E3 ubiquitin ligase inducible degrader of the low-density lipoprotein receptor (IDOL) triggers lysosomal degradation of the low-density lipoprotein receptor. The tissue-specific effects of the IDOL pathway on plasma cholesterol and atherosclerosis have not been examined.
  
  
  OBJECTIVE
  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.
  
  
  RESULTS
  We expressed a degradation-resistant, dominant-active form of IDOL (super 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 low-density lipoprotein receptor protein and increased plasma low-density lipoprotein 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 apolipoprotein E*3 Leiden mice and did not require the addition of cholate to the diet. Western diet-fed L-sIDOL mice had elevated expression of liver X receptor target genes and proinflammatory genes in their aortas.
  
  
  CONCLUSIONS
  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 low-density lipoprotein receptor regulatory pathways leading to cardiovascular disease. L-sIDOL mice are a robust, dominantly inherited, diet-inducible model for the study of atherosclerosis.
authors.affiliation: From the Departments of Pathology and Laboratory Medicine (A.C.C., S.D.L., X.-H.W., C.H., P.T.), Department of Medicine, Division of Endocrinology (J.K., C.M.W.V.S., R.I.T.), Department of Medicine, Division of Cardiology (X.-H.W., A.J.L.), and Departments of Human Genetics and Microbiology Immunology and Molecular Genetics (A.J.L.), David Geffen School of Medicine, University of California, Los Angeles; Howard Hughes Medical Institute, Los Angeles, CA (A.C.C., S.D.L., C.H., P.T.); and Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia (A.C.C.).
authors.forename: Anna C
authors.initials: AC
authors.lastname: Calkin
authors.affiliation: From the Departments of Pathology and Laboratory Medicine (A.C.C., S.D.L., X.-H.W., C.H., P.T.), Department of Medicine, Division of Endocrinology (J.K., C.M.W.V.S., R.I.T.), Department of Medicine, Division of Cardiology (X.-H.W., A.J.L.), and Departments of Human Genetics and Microbiology Immunology and Molecular Genetics (A.J.L.), David Geffen School of Medicine, University of California, Los Angeles; Howard Hughes Medical Institute, Los Angeles, CA (A.C.C., S.D.L., C.H., P.T.); and Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia (A.C.C.).
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Lee
authors.affiliation: From the Departments of Pathology and Laboratory Medicine (A.C.C., S.D.L., X.-H.W., C.H., P.T.), Department of Medicine, Division of Endocrinology (J.K., C.M.W.V.S., R.I.T.), Department of Medicine, Division of Cardiology (X.-H.W., A.J.L.), and Departments of Human Genetics and Microbiology Immunology and Molecular Genetics (A.J.L.), David Geffen School of Medicine, University of California, Los Angeles; Howard Hughes Medical Institute, Los Angeles, CA (A.C.C., S.D.L., C.H., P.T.); and Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia (A.C.C.).
authors.forename: Jason
authors.initials: J
authors.lastname: Kim
authors.affiliation: From the Departments of Pathology and Laboratory Medicine (A.C.C., S.D.L., X.-H.W., C.H., P.T.), Department of Medicine, Division of Endocrinology (J.K., C.M.W.V.S., R.I.T.), Department of Medicine, Division of Cardiology (X.-H.W., A.J.L.), and Departments of Human Genetics and Microbiology Immunology and Molecular Genetics (A.J.L.), David Geffen School of Medicine, University of California, Los Angeles; Howard Hughes Medical Institute, Los Angeles, CA (A.C.C., S.D.L., C.H., P.T.); and Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia (A.C.C.).
authors.forename: Caroline M W
authors.initials: CM
authors.lastname: Van Stijn
authors.affiliation: From the Departments of Pathology and Laboratory Medicine (A.C.C., S.D.L., X.-H.W., C.H., P.T.), Department of Medicine, Division of Endocrinology (J.K., C.M.W.V.S., R.I.T.), Department of Medicine, Division of Cardiology (X.-H.W., A.J.L.), and Departments of Human Genetics and Microbiology Immunology and Molecular Genetics (A.J.L.), David Geffen School of Medicine, University of California, Los Angeles; Howard Hughes Medical Institute, Los Angeles, CA (A.C.C., S.D.L., C.H., P.T.); and Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia (A.C.C.).
authors.forename: Xiao-Hui
authors.initials: XH
authors.lastname: Wu
authors.affiliation: From the Departments of Pathology and Laboratory Medicine (A.C.C., S.D.L., X.-H.W., C.H., P.T.), Department of Medicine, Division of Endocrinology (J.K., C.M.W.V.S., R.I.T.), Department of Medicine, Division of Cardiology (X.-H.W., A.J.L.), and Departments of Human Genetics and Microbiology Immunology and Molecular Genetics (A.J.L.), David Geffen School of Medicine, University of California, Los Angeles; Howard Hughes Medical Institute, Los Angeles, CA (A.C.C., S.D.L., C.H., P.T.); and Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia (A.C.C.).
authors.forename: Aldons J
authors.initials: AJ
authors.lastname: Lusis
authors.affiliation: From the Departments of Pathology and Laboratory Medicine (A.C.C., S.D.L., X.-H.W., C.H., P.T.), Department of Medicine, Division of Endocrinology (J.K., C.M.W.V.S., R.I.T.), Department of Medicine, Division of Cardiology (X.-H.W., A.J.L.), and Departments of Human Genetics and Microbiology Immunology and Molecular Genetics (A.J.L.), David Geffen School of Medicine, University of California, Los Angeles; Howard Hughes Medical Institute, Los Angeles, CA (A.C.C., S.D.L., C.H., P.T.); and Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia (A.C.C.).
authors.forename: Cynthia
authors.initials: C
authors.lastname: Hong
authors.affiliation: From the Departments of Pathology and Laboratory Medicine (A.C.C., S.D.L., X.-H.W., C.H., P.T.), Department of Medicine, Division of Endocrinology (J.K., C.M.W.V.S., R.I.T.), Department of Medicine, Division of Cardiology (X.-H.W., A.J.L.), and Departments of Human Genetics and Microbiology Immunology and Molecular Genetics (A.J.L.), David Geffen School of Medicine, University of California, Los Angeles; Howard Hughes Medical Institute, Los Angeles, CA (A.C.C., S.D.L., C.H., P.T.); and Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia (A.C.C.).
authors.forename: Rajendra I
authors.initials: RI
authors.lastname: Tangirala
authors.affiliation: From the Departments of Pathology and Laboratory Medicine (A.C.C., S.D.L., X.-H.W., C.H., P.T.), Department of Medicine, Division of Endocrinology (J.K., C.M.W.V.S., R.I.T.), Department of Medicine, Division of Cardiology (X.-H.W., A.J.L.), and Departments of Human Genetics and Microbiology Immunology and Molecular Genetics (A.J.L.), David Geffen School of Medicine, University of California, Los Angeles; Howard Hughes Medical Institute, Los Angeles, CA (A.C.C., S.D.L., C.H., P.T.); and Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia (A.C.C.). ptontonoz@mednet.ucla.edu.
authors.forename: Peter
authors.initials: P
authors.lastname: Tontonoz
mesh_terms: D000418:Albumins / Q000235:genetics; D000818:Animals; D001011:Aorta / Q000378:metabolism / Q000473:pathology; D001018:Aortic Diseases / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D053318:Apolipoprotein E3 / Q000235:genetics / Q000378:metabolism; D050197:Atherosclerosis / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D008078:Cholesterol, LDL / Q000097:blood; D059305:Diet, High-Fat; D066273:Diet, Western; D004195:Disease Models, Animal; D006801:Humans; D006937:Hypercholesterolemia / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D018836:Inflammation Mediators / Q000378:metabolism; D008099:Liver / Q000201:enzymology*; D000071518:Liver X Receptors; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation; D057093:Orphan Nuclear Receptors / Q000378:metabolism; D058226:Plaque, Atherosclerotic; D011401:Promoter Regions, Genetic; D011973:Receptors, LDL / Q000378:metabolism; D013997:Time Factors; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*
chemical_list: D000418:Albumins; D053318:Apolipoprotein E3; D008078:Cholesterol, LDL; D018836:Inflammation Mediators; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D011973:Receptors, LDL; C403126:MYLIP protein, human; D044767:Ubiquitin-Protein Ligases
keywords: atherosclerosis; cholesterol, LDL; ubiquitin-protein ligases