Physicians' Academy for Cardiovascular Education

ACAT Inhibitors

News - Mar. 24, 2011

ACAT Inhibitors

ACAT is a membrane-bound enzyme located in the rough endoplasmic reticulum of various tissues, where it facilitates esterifi cation of cholesterol and fatty acids into intracellular cholesterol esters. At least two isoforms of this enzyme exist: ACAT1 and ACAT2. ACAT1 regulates cholesterol homeostasis in the brain, macrophages, and adrenal glands, and ACAT2 esterifies cholesterol in the small intestine and liver. ACAT allows the production of chylomicrons in the intestine and the secretion of very low density lipoprotein (VLDL) from the liver (Fig. 2). ACAT is also responsible for the macrophage-mediated storage of cholesterol esters—a phenomenon coined foam cell formation, which plays a crucial role in atherosclerotic disease development. Therefore, inhibiting ACAT may not only lower intestinal absorption of cholesterol but may also inhibit macrophage foam cell formation. In experimental animal models, nonselective ACAT inhibitors have been shown to decrease plasma levels of LDL-C and to protect against atherosclerotic disease [41–43]. Nevertheless, human trials have been disappointing. Administering the nonselective ACAT inhibitor avasimibe to patients with coronary heart disease did not result in a decrease in plaque volume as assessed by intravascular ultrasound [44]. An 18-month trial treating patients with atherosclerotic disease with the nonselective ACAT inhibitor pactimibe likewise failed to result in reduced plaque volume and even suggested an adverse effect of the drug on the degree of atherosclerotic disease [45].

These negative results led to the discontinuation of further development of nonselective ACAT inhibitors for preventing CVD. Nevertheless, the development of selective ACAT2 inhibitors is still ongoing due to promising findings in animal studies. Mice lacking ACAT2 were protected against diet-induced hypercholesterolemia and gallstone formation [46,47]. Also, the absence of ACAT2 in the small intestine and liver almost completely prevented atherosclerosis in apo E–defi cient mice [48]. In addition, ACAT2 could be selectively inhibited in the liver with antisense oligonucleotides (ASOs) in LDL-receptor knockout mice [49]. This resulted in a signifi cant 80% reduction of ACAT2 expression, decreased diet-induced hypercholesterolemia, and reduced cholesterol ester deposition in the aorta. Despite the discrepancy between animal studies and human trials with nonselective ACAT inhibitors, these findings are encouraging and support further testing in humans.


ACAT inhibitors

Update on ACAT inhibition

Please view this educational slidekit for an update of the potential role of ACAT inhibition in lipid management

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