ACAT2 Is a Target for Treatment of Coronary Heart Disease Associated With Hypercholesterolemia

Abstract

Previous Brief Reviews in this Series:• Chen HC, Farese RV Jr. Inhibition of triglyceride synthesis as a treatment strategy for obesity: lessons from DGAT1-deficient mice. 2005;25:482-486.• Zalewski A, Macphee C. Role of lipoprotein-associated phospholipase A 2 in atherosclerosis: biology, epidemiology, and possible therapeutic target. 2005;25:923-931. ACAT2 Is a Target for Treatment of Coronary HeartDisease Associated With HypercholesterolemiaAbstract-The inhibition of intracellular cholesterol esterification as a means to prevent atherosclerosis has been considered to have potential for many years. Two different ACAT enzymes were discovered about 7 years ago, and it has become clear that the two enzymes provide separate physiologic functions. Much has been learned from mice with gene deletions for either ACAT1 or ACAT2. Deletion of ACAT2 has consistently been atheroprotective whereas deletion of ACAT1 has been varyingly problematic. ACAT1 functions in converting cellular cholesterol into cholesteryl ester in response to cholesterol abundance inside the cells. In atherosclerotic lesions, where macrophages ingest excess cholesterol, the ability to esterify the newly-acquired cholesterol seems important for cell survival. Inhibition of ACAT1 may bring undesired consequences with destabilization of cellular membrane function upon cholesterol accumulation leading to macrophage cell death. In contrast, ACAT2 is expressed only in hepatocytes and enterocytes, where ACAT1 is silent, and appears to provide cholesteryl esters for transport in lipoproteins. These two cell types have an abundance of additional mechanisms for disposing of cholesterol so that depletion of ACAT2 does not signal apoptosis. At the present time, the bulk of the available data suggest that the strategy seeming to bear the most potential for treatment of coronary heart disease associated with hypercholesterolemia would be to specifically inhibit ACAT2.

Targeted Depletion of Hepatic ACAT2-driven Cholesterol Esterification Reveals a Non-biliary Route for Fecal Neutral Sterol Loss

“…ACAT1 is ubiquitously expressed in almost all nonlipoprotein producing cell types, and acts to prevent free cholesterol-induced cytotoxicity (reviewed in Ref. 6). On the other hand ACAT2 is expressed exclusively in lipoprotein-producingcells such as intestinal enterocytes and hepatocytes in the liver (7,8), and plays a gatekeeper role in the production of atherogenic apoB-containing lipoproteins (6 -10).…”

Possible Pivotal Role of Latent Chronic T. gondii Infection in the Pathogenesis of Atherosclerosis

“…ACAT2 is expressed only in intestinal enterocytes, hepatocytes (where ACAT1 is silent [224] ), and in macrophages [152,225] . Parini et al [226] found that ACAT2 protein expression was localized to hepatocytes as the major cholesterol-esterifying enzyme in human liver, whereas ACAT1 was present in Kupfer cells only.…”

“…ACAT2 participates in: (a) the enterohepatic recirculation of cholesterol, as revealed by the reduced intestinal absorption efficiency in ACAT2-deficient mice [228] ; (b) in regulation of cholesterol metabolism within the hepatocyte; and (c) in CE secretion and transport in plasma lipoproteins [184] . ACAT2 functions in free cholesterol esterification during cholesterol absorption in the enterocyte [224] . This is a key cholesterol esterification enzyme necessary for the development of hypercholesterolemia [228] .…”

“…Most of the absorbed cholesterol is esterified by ACAT2 for incorporation into chylomicron particles, so that 75-80% of newly absorbed cholesterol transported into the body in chylomicrons as CE [229] . The metabolism of chylomicrons in the circulation leads to the formation of remnant lipoproteins that retain the CE, which is ultimately delivered to the hepatocytes in the liver [224] . The LCAT derived CE of HDL is removed from plasma primarily by the liver through selective CE uptake [230] and by whole HDL particle uptake [231] .…”

“…It was suggested that ACAT1 expression in monocytes infiltrating from the blood circulation to vascular LCAT (a liver-derived plasma protein) responsible for the synthesis of plasma lipoprotein CEs [232] are important determinants of both LDL and VLDL cholesterol concentrations and the subsequent development of atherosclerosis [233,234] . Lee et al [233] established that while ACAT2 contributed CEs to newly secreted VLDL, LCAT added CE during LDL particle formation in mice [224,233] . ACAT2 deficiency led to a marked decrease in the percentage of CEs (37.2 ± 2.1% vs 3.9 ± 0.8%) in plasma VLDL, with a concomitant increase in the percentage of triglyceride (33.0 ± 3.2% vs 66.7 ± 2.5%) [233] .…”