CI-1011 lowers lipoprotein(a) and plasma cholesterol concentrations in chow-fed cynomolgus monkeys

Ramharack, Randy; Spahr, Mark A.; Sekerke, Catherine; Stanfield, R. L.; Bousley, Richard F.; Lee, Helen T.; Krause, Brian K

doi:10.1016/s0021-9150(97)00189-5

Cited by 25 publications

(16 citation statements)

References 46 publications

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“…The majority of cholesterol delivered to the liver is esterifi ed and resides in the core of chylomicron remnants. Nonspecifi c ACAT inhibitors have been shown to decrease cholesterol absorption by 20 to 80% in rats, hamsters, rabbits, pigs, and nonhuman primates (10)(11)(12)(13)(14). Whole body ACAT2…”

Section: Immunoblottingmentioning

confidence: 99%

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

Zhang

Kelley

Marshall

et al. 2012

Journal of Lipid Research

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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-

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Section: Immunoblottingmentioning

confidence: 99%

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

Zhang

Kelley

Marshall

et al. 2012

Journal of Lipid Research

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“…Although there were no previous reports on the ability of ACAT inhibitors to modulate Lp(a), Ramharack and coworkers studied the effect of avasimibe treatment (3-30 mg/kg/day) on Lp(a) levels in chow-fed cynomolgus monkeys (58). They found that plasma Lp(a) and cholesterol levels were significantly decreased to 75 and 85% after only 1 week of treatment at the lowest dose.…”

Section: Effects On Plasma Lipid and Lipoprotein (A) Levelsmentioning

confidence: 99%

Pharmacology of the AC AT Inhibitor Avasimibe (CI‐1011)

Llaverı́as

Laguna

Alegret

2003

Cardiovascular Drug Reviews

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Avasimibe is a novel orally bioavailable ACAT inhibitor, currently under clinical development (phase III trials). It was safe when administered to rats, dogs, and humans. In vitro studies in human macrophages demonstrated that avasimibe reduces foam cell formation not only by enhancing free cholesterol efflux, but also by inhibiting the uptake of modified LDL. The concentration-dependent reduction in cellular cholesteryl ester content in these cells was not accompanied by an increase in intracellular free cholesterol, which is in agreement with a good safety profile for avasimibe. In the liver, avasimibe caused a significant reduction in the secretion of apo B and apo B-containing lipoproteins into plasma. Avasimibe induced cholesterol 7á-hydroxylase and increased bile acid synthesis in cultured rat hepatocytes, and its administration to rats did not produce an increase in lithogenicity index of the bile. The hypolipidemic efficacy of the compound was demonstrated in cholesterol-fed as well as in non-cholesterol-fed animals. In these models, plasma cholesterol levels were reduced, mainly due to the decrease in the non-HDL cholesterol fraction. Clinical data are scarce, but in a study performed in 130 men and women with combined hyperlipidemia and hypoalphalipoproteinemia, avasimibe, 50-500 mg/day, significantly reduced plasma total triglyceride and VLDL-cholesterol. Although total cholesterol, LDL-cholesterol, and HDL-cholesterol were unchanged, it must be stressed that animal data suggest that avasimibe may have direct antiatherosclerotic activity in addition to its cholesterol-lowering effect. Avasimibe treatment can also contribute to increase plaque stability, as it reduces the accumulation of lipids in the arterial wall, inhibits macrophage infiltration into the media and reduces matrix metalloproteinase expression and activity. Moreover, avasimibe and statins have been shown to have synergistic effects, and the combination therapy may not only inhibit atherosclerotic lesion 33

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“…In several species, avasimibe lowered cholesterol levels. Moreover, reduced atherogenesis was observed in mouse, hamster and rabbit, even on top of statin use [13][14][15][16][17]. Similar results were achieved with pactimibe but, unfortunately, these studies were not published.…”

Section: The Risementioning

confidence: 63%

And then there were acyl coenzyme A:cholesterol acyl transferase inhibitors

Meuwese

Franssen

Stroes

et al. 2006

Current Opinion in Lipidology

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In our opinion, the consistent negative findings in recent clinical trials have virtually eliminated the chances for this class of drugs to be introduced for cardiovascular prevention. Possible strategies focused on selective ACAT 2 inhibition or the combination of ACAT inhibitors with compounds that stimulate reverse cholesterol transport may prove to have clinical benefit. This will have to await further clinical research in humans, however, as, obviously, rodent models cannot provide reliable data as to the efficacy of this class of drugs in humans.

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CI-1011 lowers lipoprotein(a) and plasma cholesterol concentrations in chow-fed cynomolgus monkeys

Cited by 25 publications

References 46 publications

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

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

Pharmacology of the AC AT Inhibitor Avasimibe (CI‐1011)

And then there were acyl coenzyme A:cholesterol acyl transferase inhibitors

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