on May 4, 2006
Published online before print May 4, 2006, doi: 10.1161/01.ATV.0000225289.30767.06
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Submitted on March 2, 2006
Accepted on April 17, 2006
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 ;
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.
* To whom correspondence should be addressed. 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.
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