TY - JOUR
T1 - Massive xanthomatosis and atherosclerosis in cholesterol-fed low density lipoprotein receptor-negative mice
AU - Ishibashi, Shun
AU - Goldstein, Joseph L.
AU - Brown, Michael S.
AU - Herz, Joachim
AU - Burns, Dennis K.
PY - 1994/5
Y1 - 1994/5
N2 - Mice that are homozygous for a targeted disruption of the LDL receptor gene (LDLR(-/-) mice) were fed a diet that contained 1.25% cholesterol, 7.5% cocoa butter, 7.5% casein, and 0.5% cholic acid. The total plasma cholesterol rose from 246 to > 1,500 mg/dl, associated with a marked increase in VLDL, intermediate density lipoproteins (IDL), and LDL cholesterol, and a decrease in HDL cholesterol. In wild type littermates fed the same diet, the total plasma cholesterol remained < 160 mg/dl. After 7 mo, the LDLR(-/-) mice developed massive xanthomatous infiltration of the skin and subcutaneous tissue. The aorta and coronary ostia exhibited gross atheromata, and the aortic valve leaflets were thickened by cholesterol-laden macrophages. No such changes were seen in the LDLR(-/-) mice on a normal chow diet, nor in wild type mice that were fed either a chow diet or the high-fat diet. We conclude that LDL receptors are largely responsible for the resistance of wild type mice to atherosclerosis. The cholesterol-fed LDLR(-/-) mice offer a new model for the study of environmental and genetic factors that modify the processes of atherosclerosis and xanthomatosis.
AB - Mice that are homozygous for a targeted disruption of the LDL receptor gene (LDLR(-/-) mice) were fed a diet that contained 1.25% cholesterol, 7.5% cocoa butter, 7.5% casein, and 0.5% cholic acid. The total plasma cholesterol rose from 246 to > 1,500 mg/dl, associated with a marked increase in VLDL, intermediate density lipoproteins (IDL), and LDL cholesterol, and a decrease in HDL cholesterol. In wild type littermates fed the same diet, the total plasma cholesterol remained < 160 mg/dl. After 7 mo, the LDLR(-/-) mice developed massive xanthomatous infiltration of the skin and subcutaneous tissue. The aorta and coronary ostia exhibited gross atheromata, and the aortic valve leaflets were thickened by cholesterol-laden macrophages. No such changes were seen in the LDLR(-/-) mice on a normal chow diet, nor in wild type mice that were fed either a chow diet or the high-fat diet. We conclude that LDL receptors are largely responsible for the resistance of wild type mice to atherosclerosis. The cholesterol-fed LDLR(-/-) mice offer a new model for the study of environmental and genetic factors that modify the processes of atherosclerosis and xanthomatosis.
KW - animal model for atherosclerosis
KW - hypercholesterolemia
KW - lipoprotein metabolism
KW - liver receptors
KW - targeted gene disruption
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U2 - 10.1172/JCI117179
DO - 10.1172/JCI117179
M3 - Article
C2 - 8182121
AN - SCOPUS:0028345073
SN - 0021-9738
VL - 93
SP - 1885
EP - 1893
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 5
ER -