Arterioscler Thromb Vasc Biol. 2006 May 4; [Epub
ahead of print]
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.
Bell TA 3rd, Brown JM, Graham MJ, Lemonidis KM, Crooke RM, Rudel LL.
Department of Pathology, Section on Lipid Sciences, Wake Forest University Health Sciences, Winston-Salem, NC; and Cardiovascular Group, Antisense Drug Discovery, Isis Pharmaceuticals, Inc, Carlsbad, Calif.
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.
PMID: 16675724 [PubMed - as supplied by publisher] Top of For
Arterioscler Thromb Vasc Biol. 2006 May 4; [Epub ahead of print]