A MOUSE MODEL OF HUMAN FAMILIAL HYPERCHOLESTEROLEMIA - MARKEDLY ELEVATED LOW-DENSITY-LIPOPROTEIN CHOLESTEROL LEVELS AND SEVERE ATHEROSCLEROSIS ON A LOW-FAT CHOW DIET

Mutations in the low density lipoprotein (LDL) receptor gene cause fam ilial hypercholesterolemia, a human disease characterized by premature atherosclerosis and markedly elevated plasma levels of LDL cholestero l and apolipoprotein (apo) B100. In contrast, mice deficient for the L DL receptor (Ldlr(-/-)) have only mildly elevated LDL cholesterol leve ls and little atherosclerosis. This difference results from extensive editing of the hepatic apoB mRNA in the mouse, which limits apoB100 sy nthesis in favor of apoB48 synthesis. We have generated Ldlr(-/-) mice that cannot edit the apoB mRNA and therefore synthesize exclusively a poB100. These mice had markedly elevated LDL cholesterol and apoB100 l evels and developed extensive atherosclerosis on a chow diet. This aut hentic model of human familiar hypercholesterolemia will provide a new tool for studying atherosclerosis.