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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2006;26:1684.)
© 2006 American Heart Association, Inc.

Editorials

The Nine Lives of ACAT Inhibitors

Robert V. Farese, Jr

From the Gladstone Institute of Cardiovascular Disease; and the Cardiovascular Research Institute, the Departments of Medicine and Biochemistry & Biophysics, and the Diabetes Center, University of California, San Francisco.

Correspondence to Robert V. Farese Jr, University of California, San Francisco, 1650 Owens Street, San Francisco, CA 94158. E-mail bfarese@gladstone.ucsf.edu

An extract of the first 250 words of the full text is provided, because this article has no abstract.

Atherosclerosis is the product of excessive lipid accumulation and inflammation in the artery wall. The lipid that tops every list of suspects is cholesterol, which is the primary lipid in low-density lipoproteins (LDL). Cholesterol exists either as a simple molecule or as cholesterol esters, in which the hydroxyl group is linked to a fatty acyl moiety. In cells, cholesterol esters are synthesized in an intracellular reaction catalyzed by acyl coenzyme A (CoA):cholesterol acyltransferase (ACAT) enzymes.^1,2 Owing to the discoveries of cholesterol esters in arterial lesions in 1910³ and of ACAT activity in the mid 1900s,⁴ inhibiting ACAT has been considered as a strategy for preventing or treating atherosclerosis. Over the past 25 years, interest in ACAT inhibitors has waxed and waned as new studies advance knowledge in the field. Prominently reported and disappointing results from a recent human trial of an ACAT inhibitor⁵ dampened enthusiasm for this potential therapy. However, a study by Bell et al in this issue of Arteriosclerosis, Thrombosis, and Vascular Biology⁶ revives the idea of targeting ACAT enzymes and highlights a key unanswered question: Can ACAT2-specific inhibitors lower plasma cholesterol and treat or prevent atherosclerosis?

See page 1814

After the discovery of the ACAT reaction, two rationales for inhibiting ACAT emerged. One, in retrospect, was perhaps overly simplistic: blocking cholesterol esterification in macrophages would diminish macrophage "foam cell" formation and thereby decrease atherosclerotic lesion development. The other was to decrease hepatic and intestinal cholesterol ester formation, resulting in decreases in plasma levels of the atherogenic apolipoprotein . . . [Full Text of this Article]

Related Article:

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, and Lawrence L. Rudel
Arterioscler Thromb Vasc Biol 2006 26: 1814-1820. [Abstract] [Full Text] [PDF]

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