RGD Reference Report - 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.

General

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.
Authors:	Bell TA, 3RD Brown, JM Graham, MJ Lemonidis, KM Crooke, RM Rudel, LL
Citation:	Bell TA 3rd, etal., Arterioscler Thromb Vasc Biol. 2006 Aug;26(8):1814-20. Epub 2006 May 4.
RGD ID:	1601111
Pubmed:	PMID:16675724 (View Abstract at PubMed)
DOI:	DOI:10.1161/01.ATV.0000225289.30767.06 (Journal Full-text)
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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Term	Qualifier	Evidence	With	Reference	Notes	Source	Original Reference(s)
arteriosclerosis		ISO	Acat2 (Mus musculus)	1601111; 1601111		RGD
arteriosclerosis		IMP		1601111		RGD

Objects Annotated

Genes (Rattus norvegicus)

Acat2 (acetyl-CoA acetyltransferase 2)

Genes (Mus musculus)

Acat2 (acetyl-Coenzyme A acetyltransferase 2)

Genes (Homo sapiens)

ACAT2 (acetyl-CoA acetyltransferase 2)

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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.