Increased atherosclerosis in LDL receptor–null mice lacking ACAT1 in macrophages
Sergio Fazio, … , MacRae F. Linton, Robert V. Farese Jr.
Sergio Fazio, … , MacRae F. Linton, Robert V. Farese Jr.
Published January 15, 2001
Citation Information: J Clin Invest. 2001;107(2):163-171. https://doi.org/10.1172/JCI10310.
View: Text | PDF
Article

Increased atherosclerosis in LDL receptor–null mice lacking ACAT1 in macrophages

Abstract

During atherogenesis, circulating macrophages migrate into the subendothelial space, internalize cholesterol-rich lipoproteins, and become foam cells by progressively accumulating cholesterol esters. The inhibition of macrophage acyl coenzyme A:cholesterol acyltransferase (ACAT), which catalyzes the formation of cholesterol esters, has been proposed as a strategy to reduce foam cell formation and to treat atherosclerosis. We show here, however, that hypercholesterolemic LDL receptor–deficient (LDLR–/–) mice reconstituted with ACAT1-deficient macrophages unexpectedly develop larger atherosclerotic lesions than control LDLR–/– mice. The ACAT1-deficient lesions have reduced macrophage immunostaining and more free cholesterol than control lesions. Our findings suggest that selective inhibition of ACAT1 in lesion macrophages in the setting of hyperlipidemia can lead to the accumulation of free cholesterol in the artery wall, and that this promotes, rather than inhibits, lesion development.

Authors

Sergio Fazio, Amy S. Major, Larry L. Swift, Linda A. Gleaves, Michel Accad, MacRae F. Linton, Robert V. Farese Jr.

×

Figure 4

Options: View larger image (or click on image) Download as PowerPoint
Movat’s pentachrome staining of aortic cross sections from representativ...
Movat’s pentachrome staining of aortic cross sections from representative LDLR–/– mice after western-type diet. The left panel shows a representative section from a recipient of ACAT1+/+ wild-type marrow, whereas the right panel shows a recipient of ACAT1–/– marrow. The lesion area in the control animal is highly cellular, and amorphous material is detected in the deeper portion of the plaque. This phenomenon is exaggerated in the ACAT1–/– recipient mouse, where lesions are thicker, less cellular, and more enriched in extracellular material than in controls. Nuclei are stained black, and smooth muscle cells are stained red. The blue stain indicates ground substance and mucins. The lack of yellow stain indicates the absence of significant collagen deposition. In each panel, the section is oriented with the lumen on top and the media at the bottom.