Massive xanthomatosis and atherosclerosis in cholesterol-fed low density lipoprotein receptor-negative mice.
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.
Ishibashi
S
S
Department of Molecular Genetics, University of Texas Southwestern Medical Center at Dallas 75235.
Goldstein
J L
JL
Brown
M S
MS
Herz
J
J
Burns
D K
DK
D000818:Animals; D001011:Aorta / Q000473:pathology; D001161:Arteriosclerosis / Q000209:etiology*; D002784:Cholesterol / Q000097:blood; D002791:Cholesterol, Dietary / Q000378:metabolism*; D007113:Immunity, Innate; D008074:Lipoproteins / Q000097:blood; D051379:Mice; D018345:Mice, Knockout; D009206:Myocardium / Q000473:pathology; D011973:Receptors, LDL / Q000172:deficiency* / Q000235:genetics; D012867:Skin / Q000473:pathology; D014973:Xanthomatosis / Q000209:etiology*
D002791:Cholesterol, Dietary; D008074:Lipoproteins; D011973:Receptors, LDL; D002784:Cholesterol