Tissue-specific knockouts of ACAT2 reveal that intestinal depletion is sufficient to prevent diet-induced cholesterol accumulation in the liver and blood

Abstract

This article is available online at http://www.jlr.org Supplementary key words Acyl-CoA:cholesterol acyltransferase • cholesteryl ester • lipids and lipoproteins • atherosclerosis Acyl-CoA:cholesterol acyltransferase (ACAT), also known as sterol O-acyltransferase, is a microsomal protein responsible for intracellular cholesterol ester (CE) synthesis. ACAT typically uses monounsaturated fatty acids, such as oleate from the acyl-CoA pool together with free cholesterol (FC) as substrates. Two subtypes of ACAT exist: ACAT1 is expressed in a variety of tissues, and ACAT2 is expressed exclusively in enterocyte of the intestine and hepatocyte of the liver, where one of its roles is to generate CE for packaging into chylomicrons and very low-density lipoproteins (VLDLs), respectively ( 1 ). Cholesterol ester, especially cholesterol oleate, is one of the major components of atherosclerotic plaques and, when found in apoBcontaining lipoproteins, may play a critical role in the pathogenesis of atherosclerosis ( 2 ).Deletion of ACAT2 in LDLr Ϫ / Ϫ mice led to a 78% decrease of aortic surface area as lesion and an 88% decrease in CE deposited in atherosclerotic plaques ( 3 ). The proatherogenic effect of ACAT2-derived CE also was found in APOE Ϫ / Ϫ mice after ACAT2 was deleted, and atherosclerosis was almost absent ( 4 ). These data indicate a critical role of CE as a sensitive marker in atherosclerotic lesion development. In the past few years, the role of hepatic ACAT2 on cholesterol homeostasis has been extensively studied using an antisense oligonucleotide (ASO)-mediated knockdown in mice ( 5-7 ). ASO-mediated hepatic ACAT2 depletion resulted in the lack of hepatic CE production, Abstract Acyl-CoA:cholesterol acyltransferase 2 (ACAT2) generates cholesterol esters (CE) for packaging into newly synthesized lipoproteins and thus is a major determinant of blood cholesterol levels. ACAT2 is expressed exclusively in the small intestine and liver, but the relative contributions of ACAT2 expression in these tissues to systemic cholesterol metabolism is unknown. We investigated whether CE derived from the intestine or liver would differentially affect hepatic and plasma cholesterol homeostasis. We gen-

PRD125, a Potent and Selective Inhibitor of SterolO-Acyltransferase 2 Markedly Reduces Hepatic Cholesteryl Ester Accumulation and Improves Liver Function in Lysosomal Acid Lipase-Deficient Mice

“…This conclusion stems from a plethora of studies in various in vitro systems and animal models, particularly mouse models with liver-or intestinespecific deletion of SOAT2 (Zhang et al, 2012). The secretion from the liver of VLDL with a reduced EC content would potentially lower the amount of EC carried in mature LDL particles and VLDL remnants that are subsequently cleared from the circulation primarily by the liver, but also by the small intestine and other organs (Osono et al, 1995).…”

New Pyripyropene A Derivatives, Highly SOAT2-Selective Inhibitors, Improve Hypercholesterolemia and Atherosclerosis in Atherogenic Mouse Models

“…Accordingly, K-604, a potent SOAT1-selective inhibitor, also recently failed in phase II, although these clinical data and the reason for failure have not yet been reported. On the other hand, PRDs that only affected SOAT2-expressing small intestines and livers and showed no effects on SOAT1-expressing macrophages and adrenal glands in in vitro and in vivo study performed as predicted from SOAT2 studies, New Pyripyropene A Derivatives Improve Atherosclerosis including SOAT2 knockout mouse studies (Buhman et al, 2000;Willner et al, 2003;Bell et al, 2006Bell et al, , 2007Zhang et al, 2012Zhang et al, , 2014. These findings strongly suggest that potent SOAT2-selective inhibition and PRDs can be effective and very safe in human patients.…”

“…Furthermore, intestine-specific SOAT2 knockout mice had reduced cholesterol absorption, and liver-specific SOAT2 knockout mice had a significant reduction in very-low-density lipoprotein (VLDL) concentration (Zhang et al, 2012). These mice were equally protected from diet-induced hepatic CE accumulation and hypercholesterolemia (Zhang et al, 2012).…”

“…SOAT knockout mouse studies indicated that SOAT1-selective inhibition might cause detrimental effects Yagyu et al, 2000;Fazio et al, 2001), whereas SOAT2-selective inhibition consistently showed atheroprotective activity without side effects (Buhman et al, 2000;Willner et al, 2003;Zhang et al, 2014). Furthermore, intestine-specific SOAT2 knockout mice had reduced cholesterol absorption, and liver-specific SOAT2 knockout mice had a significant reduction in very-low-density lipoprotein (VLDL) concentration (Zhang et al, 2012). These mice were equally protected from diet-induced hepatic CE accumulation and hypercholesterolemia (Zhang et al, 2012).…”

An ACAT-1Inhibitor, K-604, Ameliorates Hepatic Inflammation in NAFLD and NASH Models

“…This indicates that a potent inhibition of ACAT-1 (100 mg/ kg) may promote favorable effects on lipid metabolism in the ZF rats. We noted that genetic deletion of ACAT-2 or treatment with antisense oligonucleotides of ACAT-2 could protect the mouse liver from dietary cholesterol-induced steatosis by facilitating TG secretion to the plasma [36,37]. In the mouse liver, ACAT-2 is primarily expressed in hepatocytes [7].…”