Eliminating Atherogenesis in Mice by Switching Off Hepatic Lipoprotein Secretion

Abstract

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.

Emigration of monocyte-derived cells from atherosclerotic lesions characterizes regressive, but not progressive, plaques

“…Cholesterol levels do not drop in apoE Ϫ/Ϫ recipients (12). Transfer of these lesion-rich aortic arches into WT recipients (C57BL͞6 apoE ϩ/ϩ ) results in an immediate conversion to normal lipid profiles, which in turn promotes lesion regression (12), in agreement with nonsurgical methods that restore normal blood lipid profiles and͞or apoE (23,24). Significant changes in lesion area were observed by or before 2 weeks after surgical transfer (Fig.…”

Antisense inhibition of proprotein convertase subtilisin/kexin type 9 reduces serum LDL in hyperlipidemic mice

“…A reduction in HDL has also been observed in Pcsk9-deficient mice (3), and those authors suggested that this results from enhanced clearance of apoE-containing lipoproteins facilitated by increased hepatic LDLR abundance. Furthermore, Lieu et al (10) reported similar findings in Reversa mice and suggested that HDL particle formation requires components derived from apoB-associated lipoproteins. Serum free cholesterol and phospholipids were reduced as well [25% (P , 0.005) and 54% (P , 0.0001), respectively].…”

siRNA-induced liver ApoB knockdown lowers serum LDL-cholesterol in a mouse model with human-like serum lipids

“…In the same report, Crooke reported that Apoe -defi cient mice were the least sensitive to the lipid-lowering effects of ApoB ASO, with serum TC being reduced by 25% and LDL by 40%. It has been suggested that mature HDL particles require components of apoB-containing lipoproteins, so that a signifi cant loss of VLDL and LDL results in a reduction in the number of HDL particles ( 36 ). Alternatively, reduction in the secretion of hepatic ApoB may allow secreted ApoE to associate more readily with HDL particles in circulation and thus redirect HDL particles to a clearance via LDL receptors.…”