A direct role for the macrophage low density lipoprotein receptor in atherosclerotic lesion formation

To evaluate the contribution of the macrophage low density lipoprotein rece ptor (LDLR) to atherosclerotic lesion formation, we performed bone marrow t ransplantation studies in different mouse strains. First, LDLR(-/-) mice we re transplanted with either LDLR(+/+) marrow or LDLR(-/-) marrow and were c hallenged with an atherogenic Western type diet. The diet caused severe hyp ercholesterolemia of a similar degree in the two groups, and no differences in the aortic lesion area were detected. Thus, macrophage LDLR expression does not influence foam cell lesion formation in the setting of extreme LDL accumulation. To determine whether macrophage LDLR expression affects foam cell formation under conditions of moderate, non-LDL by. perlipidemia, we transplanted C57BL/6 mice with either LDLR(-/-) marrow (experimental group) or LDLR(+/+) marrow (controls). Cholesterol levels were not significantly different between the two groups at baseline or after 6 weeks on a butterfa t diet, but were 40% higher in the experimental mice after 13 weeks, mostly due to accumulation of beta-very low density lipoprotein (beta-VLDL). Desp ite the increase in cholesterol levels, mice receiving LDLR(-/-) marrow dev eloped 63% smaller lesions than controls, demonstrating that macrophage LDL R affects the rate of foam cell formation when the atherogenic stimulus is beta-VLDL. We conclude that the macrophage LDLR is responsible for a signif icant portion of lipid accumulation in foam cells under conditions of dieta ry stress.