Published Online
on February 17, 2003

A more recent version of this article appeared on March 11, 2003

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Submitted on October 22, 2002
Accepted on December 6, 2002

Eliminating Atherogenesis in Mice by Switching Off Hepatic Lipoprotein Secretion

Hsiao D. Lieu MD^*, Shannon K. Withycombe BS, Quinn Walker BS, James X. Rong PhD, Rosemary L. Walzem PhD, Jinny S. Wong MA, Robert L. Hamilton PhD, Edward A. Fisher MD, PhD, and Stephen G. Young MD

From the Gladstone Institute of Cardiovascular Disease (H.D.L., S.K.W., Q.W., S.G.Y.); the Cardiovascular Research Institute, University of California, San Francisco (H.D.L., S.G.Y., J.S.W., R.L.H.); the Department of Medicine, University of California, San Francisco (H.D.L., S.G.Y.); and the Department of Anatomy, University of California, San Francisco (R.L.H.), San Francisco, Calif; the Poultry Science Department, Texas A&M University, College Station, Tex (R.L.W.); and the Cardiovascular Institute and Department of Medicine, Mount Sinai School of Medicine, New York, NY (J.X.R., E.A.F.).

^* To whom correspondence should be addressed. E-mail: hlieu{at}gladstone.ucsf.edu.

Background--LDL receptor-deficient "apolipoprotein (apo)-B100-only" mice (Ldlr^-/-Apob^100/100 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^-/-Apob^100/100 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.

Key words: cholesterol • hypercholesterolemia • apolipoproteins • lipoproteins • atherosclerosis

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