Massive xanthomatosis and atherosclerosis in cholesterol-fed low density lipoprotein receptor-negative mice

J Clin Invest. 1994 May;93(5):1885-93. doi: 10.1172/JCI117179.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Aorta / pathology
  • Arteriosclerosis / etiology*
  • Cholesterol / blood
  • Cholesterol, Dietary / metabolism*
  • Immunity, Innate
  • Lipoproteins / blood
  • Mice
  • Mice, Knockout
  • Myocardium / pathology
  • Receptors, LDL / deficiency*
  • Receptors, LDL / genetics
  • Skin / pathology
  • Xanthomatosis / etiology*

Substances

  • Cholesterol, Dietary
  • Lipoproteins
  • Receptors, LDL
  • Cholesterol