Background-LDL receptor-deficient "apolipoprotein (apo)-B100 -only" mice (Ldlr Ϫ/Ϫ 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 LdlrϪ/Ϫ 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 233.9Ϯ46.0 to 37.2Ϯ6.5 mg/dL. In mice fed a high-fat diet, cholesterol levels fell from 525.7Ϯ32.2 to 100.6Ϯ14.3 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.

The genes for apolipoprotein B and microsomal triglyceride transfer protein are expressed in mouse and human heart tissue. Why the heart would express these "lipoprotein assembly" genes has been unclear. Here we demonstrate that the beating mouse heart actually secretes spherical lipoproteins. Moreover, increased cardiac production of lipoproteins (e.g., in mice that express a human apolipoprotein B transgene) was associated with increased triglyceride secretion from the heart and decreased stores of triglycerides within the heart. Increased cardiac production of lipoproteins also reduced the pathological accumulation of triglycerides that occurs in the hearts of mice lacking long-chain acyl coenzyme A dehydrogenase. In contrast, blocking heart lipoprotein secretion (e.g., in heart-specific microsomal triglyceride transfer protein knockout mice) increased cardiac triglyceride stores. Thus, heart lipoprotein secretion helps regulate cardiac triglyceride stores and may protect the heart from the detrimental effects of surplus lipids.

Abstract-Two hypercholesterolemic mouse models, the apo-E-deficient mouse (Apoe Ϫ/Ϫ ) and the LDL receptor-deficient mouse (Ldlr Ϫ/Ϫ ), have been used extensively as animal models of atherogenesis. Total plasma cholesterol levels in chow-fed Apoe Ϫ/Ϫ mice are much higher than in Ldlr Ϫ/Ϫ mice. In a recent study, we managed to even-up the cholesterol levels in Apoe