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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2007;27:1396.)
© 2007 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Dietary Fat–Induced Alterations in Atherosclerosis Are Abolished by ACAT2-Deficiency in ApoB100 Only, LDLr^–/– Mice

Thomas A. Bell, III; Kathryn Kelley; Martha D. Wilson; Janet K. Sawyer; Lawrence L. Rudel

From the Wake Forest University School of Medicine, Department of Pathology, Section on Lipid Sciences, Winston-Salem, NC.

Correspondence to Dr Lawrence L. Rudel, Wake Forest University School of Medicine, Department of Pathology/Lipid Sciences, Medical Center Blvd, Winston-Salem, NC 27157. E-mail lrudel{at}wfubmc.edu

Objectives— The enzyme acyl-coenzymeA (CoA):cholesterol O-acyltransferase 2 (ACAT2) in the liver synthesizes cholesteryl esters (CE) from cholesterol and fatty acyl-CoA, which get incorporated into apoB-containing lipoproteins that are secreted into the bloodstream. Dietary fatty acid composition influences the amount and fatty acid composition of CE within apoB-containing lipoproteins. We hypothesized that when ACAT2 activity is removed by gene deletion, hepatic CE synthesis and secretion would be minimal and, as a result, dietary fat-related differences in atherosclerosis would be eliminated.

Methods and Results— Groups of female apoB100 only, LDLr^–/– mice with and without ACAT2 were fed diets enriched in either -3 or -6 polyunsaturated fat, saturated fat, and cis or trans monounsaturated fat. After 20 weeks on diet, mice fed diets enriched in monounsaturated or saturated fat exhibited significantly higher amounts of plasma cholesterol, larger LDL particles enriched in monounsaturated CE, and more atherosclerosis than mice fed polyunsaturated fat. The dietary fat-induced shifts in plasma cholesterol, LDL size, LDL CE composition, and atherosclerosis were not observed in ACAT2^–/– mice. Regardless of the diet fed, the ACAT2^–/– mice were protected from atherosclerosis.

Conclusions— The results indicate that in apoB100 only, LDLr^–/– mice, ACAT2 plays an essential role in facilitating dietary fat type–specific atherosclerosis through its various effects on plasma lipoprotein concentration and composition.

When ACAT2 was removed by gene deletion in apoB100 only,LDLr^–/– mice, the ability of any of several types of dietary fat to induce atherosclerosis was prevented. LDL concentration, CE composition, and particle size were modified in ACAT2^–/– mice; these changes appeared to play an important role in limiting atherogenesis.

Key Words: ACAT2 • cholesteryl esters • lipoproteins • liver • aortic atherosclerosis

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