title: Eliminating atherogenesis in mice by switching off hepatic lipoprotein secretion.
abstract: BACKGROUND
  LDL receptor-deficient "apolipoprotein (apo)-B100-only" mice (Ldlr-/-Apob100/100 have elevated LDL cholesterol levels on a chow diet and develop severe aortic atherosclerosis. We hypothesized that both the hypercholesterolemia and the susceptibility to atherosclerosis could be eliminated by switching off hepatic lipoprotein production.
  
  
  RESULTS
  We bred Ldlr-/-Apob100/100 mice that were homozygous for a conditional allele for Mttp (the gene for microsomal triglyceride transfer protein) and the inducible Mx1-Cre transgene. In these animals, which we called "Reversa mice," the hypercholesterolemia could be reversed, without modifying the diet or initiating a hypolipidemic drug, by the transient induction of Cre expression in the liver. After Cre induction, hepatic Mttp expression was virtually eliminated (as judged by quantitative real-time PCR), hepatic lipoprotein secretion was abolished (as judged by electron microscopy), and LDLs were virtually eliminated from the plasma. Intestinal lipoprotein production was unaffected. In mice fed a chow diet, Cre induction reduced plasma cholesterol levels from 233.9+/-46.0 to 37.2+/-6.5 mg/dL. In mice fed a high-fat diet, cholesterol levels fell from 525.7+/-32.2 to 100.6+/-14.3 mg/dL. The elimination of hepatic lipoprotein production completely prevented both the development of atherosclerosis and the changes in gene expression that accompany atherogenesis.
  
  
  CONCLUSIONS
  We developed mice in which hypercholesterolemia can be reversed with a genetic switch. These mice will be useful for understanding gene-expression changes that accompany the reversal of hypercholesterolemia and atherosclerosis.
authors.affiliation: Gladstone Institute of Cardiovascular Disease, San Francisco, CA 94141-9100, USA. hlieu@gladstone.ucsf.edu
authors.forename: Hsiao D
authors.initials: HD
authors.lastname: Lieu
authors.forename: Shannon K
authors.initials: SK
authors.lastname: Withycombe
authors.forename: Quinn
authors.initials: Q
authors.lastname: Walker
authors.forename: James X
authors.initials: JX
authors.lastname: Rong
authors.forename: Rosemary L
authors.initials: RL
authors.lastname: Walzem
authors.forename: Jinny S
authors.initials: JS
authors.lastname: Wong
authors.forename: Robert L
authors.initials: RL
authors.lastname: Hamilton
authors.forename: Edward A
authors.initials: EA
authors.lastname: Fisher
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Young
mesh_terms: D000818:Animals; D053299:Apolipoprotein B-100; D001055:Apolipoproteins B / Q000235:genetics; D001158:Arteries / Q000378:metabolism; D001161:Arteriosclerosis / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D002352:Carrier Proteins / Q000235:genetics*; D002784:Cholesterol / Q000097:blood; D022781:Hepatocytes / Q000378:metabolism / Q000648:ultrastructure; D006937:Hypercholesterolemia / Q000097:blood / Q000628:therapy; D019426:Integrases / Q000235:genetics / Q000378:metabolism; D008055:Lipids / Q000097:blood; D008074:Lipoproteins / Q000737:chemistry / Q000378:metabolism* / Q000648:ultrastructure; D008099:Liver / Q000378:metabolism*; D051379:Mice; D010316:Particle Size; D011070:Poly I-C / Q000494:pharmacology; D011973:Receptors, LDL / Q000235:genetics; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D053299:Apolipoprotein B-100; D001055:Apolipoproteins B; D002352:Carrier Proteins; D008055:Lipids; D008074:Lipoproteins; D011973:Receptors, LDL; D014764:Viral Proteins; C106092:microsomal triglyceride transfer protein; D002784:Cholesterol; C045073:Cre recombinase; D019426:Integrases; D011070:Poly I-C