Lipoprotein size and susceptibility to atherosclerosis--insights from genetically modified mouse models.

High plasma levels of the apo-B-containing lipoproteins are casually implicated in the pathogenesis of atherosclerosis. This finding, backed by decades of animal and human studies, has sparked interest in defining which classes of apo-B-containing lipoprotein particles are most atherogenic. Although small LDL particles and larger remnant lipoproteins both appear to be atherogenic, it has been difficult to discern which particles are the most atherogenic. Here, we summarize several mouse models that have provided insights into this issue. The influence of lipoprotein size on susceptibility to atherosclerosis was examined by studying the phenotypes of two strains of mice with virtually identical levels of plasma cholesterol--Ldlr(-/-)Apob(100/100) and Apoe(-/-) Apob(100/100) mice. The Ldlr(-/-) Apob(100/100) mice, where the cholesterol is in small LDL particles, had far more atherosclerosis than Apoe(-/-) Apob(100/100) mice, where virtually all of the cholesterol was in larger, VLDL-sized particles. Another intriguing animal model is the Gpihbp1-deficient mouse. GPIHBP1 is an endothelial cell platform for lipolysis, and mice lacking this protein have an accumulation of large, triglyceride-rich lipoproteins. Defining the extent of atherosclerosis in these mice should provide new insights into the atherogenicity of large, triglyceride-rich lipoproteins.