Eliminating atherogenesis in mice by switching off hepatic lipoprotein secretion. Academic Article uri icon

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.

published proceedings

  • Circulation

author list (cited authors)

  • Lieu, H. D., Withycombe, S. K., Walker, Q., Rong, J. X., Walzem, R. L., Wong, J. S., ... Young, S. G.

citation count

  • 99

complete list of authors

  • Lieu, Hsiao D||Withycombe, Shannon K||Walker, Quinn||Rong, James X||Walzem, Rosemary L||Wong, Jinny S||Hamilton, Robert L||Fisher, Edward A||Young, Stephen G

publication date

  • March 2003