RESUMO
Two hypercholesterolemic mouse models, the apo-E-deficient mouse (Apoe(-/-)) and the LDL receptor-deficient mouse (Ldlr(-/-)), have been used extensively as animal models of atherogenesis. Total plasma cholesterol levels in chow-fed Apoe(-/-) mice are much higher than in Ldlr(-/-) mice. In a recent study, we managed to even-up the cholesterol levels in Apoe(-/-) mice and Ldlr(-/-) mice by making both models homozygous for the Apob(100) (apo B-100-only) allele. On a chow diet, apo-E-deficient apo B-100-only mice (Apoe(-/-)Apob(100/100)) and LDL receptor-deficient apo B-100-only mice (Ldlr(-/-)Apob(100/100)) had similar total plasma cholesterol levels ( approximately 300 mg/dL). The plasma of Ldlr(-/-)Apob(100/100) mice contained large numbers of small lipoproteins, whereas the plasma of Apoe(-/-)Apob(100/100) mice contained much lower levels of much larger lipoproteins. Interestingly, the Ldlr(-/-)Apob(100/100) mice developed far more extensive atherosclerotic lesions than the Apoe(-/-)Apob(100/100) mice. The finding of substantially more atherosclerosis in Ldlr(-/-)Apob(100/100) mice than in Apoe(-/-)Apob(100/100) mice, despite nearly identical cholesterol levels, suggests that large numbers of small apo B-100-containing lipoproteins are far more atherogenic than lower numbers of large apo B-100-containing lipoproteins.
Assuntos
Apolipoproteínas E/genética , Arteriosclerose/etiologia , Lipoproteínas/química , Receptores de LDL/genética , Animais , Apolipoproteína B-100 , Apolipoproteínas B/genética , Arteriosclerose/sangue , Arteriosclerose/patologia , Colesterol/sangue , Modelos Animais de Doenças , Suscetibilidade a Doenças , Homozigoto , Camundongos , Camundongos KnockoutRESUMO
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.