References
Query Results -- Details
MGI Accession ID: MGI:3050269
J Number: J:91722
Other Accession IDs:
Title: Eliminating atherogenesis in mice by switching off hepatic lipoprotein secretion.
Authors: Lieu HD; Withycombe SK; Walker Q; Rong JX; Walzem RL; Wong JS; Hamilton RL; Fisher EA; Young SG
Journal: Circulation
Volume: 107
Issue: 9
Date: 2003 Mar 11
Year: 2003
Pages: 1315-21
Review Status: Peer Reviewed
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. METHODS AND 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.
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