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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2006;26:1814.)
© 2006 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Liver-Specific Inhibition of Acyl-Coenzyme A:Cholesterol Acyltransferase 2 With Antisense Oligonucleotides Limits Atherosclerosis Development in Apolipoprotein B100–Only Low-Density Lipoprotein Receptor^–/– Mice

Thomas A. Bell, III; J. Mark Brown; Mark J. Graham; Kristina M. Lemonidis; Rosanne M. Crooke; Lawrence L. Rudel

From the Department of Pathology (T.A.B., J.M.B., L.L.R.), Section on Lipid Sciences, Wake Forest University Health Sciences, Winston-Salem, NC; and Cardiovascular Group (M.J.G., K.M.L., R.M.C.), Antisense Drug Discovery, Isis Pharmaceuticals, Inc, Carlsbad, Calif.

Correspondence to Lawrence Rudel, Department of Pathology, Section on Lipid Sciences, Wake Forest University Health Sciences, Medical Center Blvd, Winston-Salem, NC 27157. E-mail lrudel{at}wfubmc.edu

Objective— The purpose of this study was to determine the effects of liver-specific inhibition of acyl-coenzyme A:cholesterol acyltransferase 2 (ACAT2) on the development of hypercholesterolemia and atherosclerosis in mice.

Methods and Results— Apolipoprotein B100–only low-density lipoprotein (LDL) receptor^–/– mice were given saline, a nontargeting control antisense oligonucleotide (ASO), or ASOs targeting ACAT2 biweekly for a period spanning 16 weeks. Mice treated with ACAT2 targeting ASOs had liver-specific reduction in ACAT2 mRNA, yet intestinal ACAT2 and cholesterol absorption was left undisturbed. ASO-mediated knockdown of ACAT2 resulted in reduction of total plasma cholesterol, increased levels of plasma triglyceride, and a shift in LDL cholesteryl ester (CE) fatty acid composition from mainly saturated and monounsaturated to polyunsaturated fatty acid enrichment. Furthermore, the liver-specific depletion of ACAT2 resulted in protection against diet-induced hypercholesterolemia and aortic CE deposition. This is the first demonstration that specific pharmacological inhibition of ACAT2, without affecting ACAT1, is atheroprotective.

Conclusions— Hepatic ACAT2 plays a critical role in driving the production of atherogenic lipoproteins, and therapeutic interventions, such as the ACAT2-specific ASOs used here, which reduce acyltransferase 2 (ACAT2) function in the liver without affecting ACAT1, may provide clinical benefit for cardiovascular disease prevention.

Liver-specific inhibition of acyl-CoA:cholesterol acyltransferase 2 using antisense oligonucleotides was found to be effective in reducing plasma cholesterol, increasing plasma triglycerides, and shifting LDL cholesteryl ester fatty acids to become mainly polyunsaturated. These changes resulted in a reduction of aortic atherosclerosis in apoB100-only LDLr^–/– mice.

Key Words: cholesteryl esters • lipoproteins • atherosclerosis • gene expression • antisense

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