Dietary ethanol-induced modifications in hyperlipoproteinemia and atherosclerosis in nonhuman primates (Macaca nemestrina).

Rudel, L L; Leathers, C. W.; Bond, M. Gene; Bullock, Bill C.

doi:10.1161/01.atv.1.2.144

Cited by 70 publications

(17 citation statements)

References 17 publications

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“…Therefore, the differences observed in the rate of accumulation of cholesterol in the perfusates are primarily due to differences in the hepatic secretion rate of cholesteryl esters (Table III). The increase in size of plasma LDL in cholesterolfed monkeys has been shown to be primarily due to an increased number of cholesteryl oleate and cholesteryl palmitate molecules per LDL particle (2,41). Thus, the cholesteryl esters that increase in number in large molecular weight LDL are more likely to have been formed by acyl-CoA cholesteryl O-acyltransferase than by LCAT (42,43 The only form of apo B that was detected on the perfusate lipoproteins including the VLDL was the large molecular weight form, apo Bloo, termed apo B-1 in Fig.…”

Section: Resultsmentioning

confidence: 99%

“…The hypercholesterolemia that develops when nonhuman primates are fed a high-fat, high-cholesterol diet is consistently characterized by an increase in the molecular weight of plasma low density lipoprotein (LDL) (1,2). The increase in LDL molecular weight has been found to be highly correlated with the severity of coronary artery atherosclerosis (2)(3)(4).…”

Section: Introductionmentioning

confidence: 99%

“…The increase in LDL molecular weight has been found to be highly correlated with the severity of coronary artery atherosclerosis (2)(3)(4). Most of the increase in LDL size appears to be due to an increase in the cholesteryl ester content of the core of the particle, together with an increase in polar lipids and protein sufficient to maintain a 21-A-thick coat (1).…”

Section: Introductionmentioning

confidence: 99%

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Studies on the production of low density lipoproteins by perfused livers from nonhuman primates. Effect of dietary cholesterol.

Johnson¹,

Clair²,

Rudel³

1983

J. Clin. Invest.

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A B S T R A C T Nonhuman primates consuming diets containing cholesterol develop coronary artery atherosclerosis that we have found to be highly correlated with an increase in the size and cholesteryl ester content of plasma low density lipoproteins (LDL). The present studies were designed to determine whether the enlarged plasma LDL are produced directly by the liver of cholesterol-fed monkeys. African green monkeys were fed a diet containing 40% of calories as butter fat and either 0.16 mg cholesterol/kcal (control diet) or 0.78 mg cholesterol/kcal (test diet). The livers of these monkeys were perfused by recirculation with a lipoprotein-free medium for 4 h. The rate of accumulation of perfusate cholesterol was linear and greater in liver perfusates from test diet-fed vs. control diet-fed monkeys and was positively correlated with both the plasma cholesterol concentration and LDL size in the donor animal. All perfusate d < 1.063 g/ ml lipoprotein subfractions from livers of test diet-fed monkeys were enriched in cholesteryl ester severalfold over the corresponding subfractions from control dietfed monkeys and contained only the larger form of apolipoprotein B typical of plasma LDL. However, the perfusate lipoproteins in the LDL density range did not have an average size or composition typical of LDL from plasma. Rather, they were relatively enriched in phospholipid and unesterified cholesterol and were deficient in cholesteryl esters. In addition, perfusate high density lipoproteins were discoidal particles. These data show that the enzyme lecithin:cholesterol acyltransferase (LCAT) was essentially inactive in Received for publication 20 December 1982 and in revised form 9 March 1983. these perfusates and, as a result, the dietary cholesterol-induced enrichment of perfusate d < 1.063 g/ml lipoproteins with cholesteryl esters probably resulted from increased hepatic secretion of cholesteryl esters and not from modification of lipoproteins by LCAT during recirculating perfusion. In spite of this increase, enlarged cholesteryl ester-rich LDL were not found in the perfusate, suggesting that large molecular weight plasma LDL are not directly secreted by the liver but instead probably result from further intravascular metabolism of cholesteryl ester-enriched hepatic precursor lipoproteins.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Studies on the production of low density lipoproteins by perfused livers from nonhuman primates. Effect of dietary cholesterol.

Johnson¹,

Clair²,

Rudel³

1983

J. Clin. Invest.

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“…Evidence in nonhuman primate models has been obtained over the past two decades indicating that the accumulation of cholesteryl esters in low density lipoprotein, with the associated low density lipoprotein particle enlargement, is highly correlated with the extent of coronary artery atherosclerosis (35)(36)(37)(38). Most recently, we have shown that the secretion of cholesteryl esters from the liver, as monitored during isolated liver perfusion, is correlated with the enrichment of the low density lipoprotein particles with cholesteryl esters and is also predictive of the extent of coronary artery atherosclerosis (12).…”

Section: Discussionmentioning

confidence: 99%

Identification of a Form of Acyl-CoA:Cholesterol Acyltransferase Specific to Liver and Intestine in Nonhuman Primates

Anderson¹,

Joyce²,

Davis³

et al. 1998

Journal of Biological Chemistry

283

212

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The present study demonstrates that two different forms of the intracellular cholesterol esterification enzyme acyl-CoA:cholesterol acyltransferase (ACAT) are present in the nonhuman primate hepatocyte; one is similar to that originally cloned from human genomic DNA, here termed ACAT1, while a second gene product, termed ACAT2, is reported here. The primate ACAT2 gene product was cloned from an African green monkey liver cDNA library. Sequence analysis of an isolated, full-length clone of ACAT2 cDNA identified an open reading frame encoding a 526-amino acid protein with essentially no sequence similarity to the ACAT1 cDNA over the N-terminal 101 amino acids but with 57% identity predicted over the remaining 425 amino acids. Transfection of the cloned ACAT2 cDNA into two different mammalian cell types resulted in the production of abundant ACAT activity which was sensitive to ACAT inhibitors. Northern blot analysis showed that the ACAT2 mRNA was expressed primarily in liver and intestine in monkeys. In contrast, ACAT1 mRNA was expressed in almost all tissues examined. Topologic predictions from the amino acid sequence of ACAT2 indicates that it has seven trans-membrane domains in a configuration that places the putative active site of the enzyme in the lumen of the endoplasmic reticulum. This orientation of ACAT2 in the endoplasmic reticulum membrane, in addition to its expression only in liver and intestine, suggests that this enzyme may have as a primary function, the secretion of cholesteryl esters into apoB-containing lipoproteins.The intracellular formation of cholesteryl esters catalyzed by the action of the enzyme acyl-CoA:cholesterol acyltransferase (ACAT; EC 2.3.1.26) 1 appears to be nearly ubiqitous in mammalian cells (1). Elucidation of the details of the structure and catalytic mechanism of ACAT and of the regulation of its activity have been stymied by the difficulty in isolating and purifying an active form of this membrane-associated enzyme. It has taken the isolation of a cDNA for ACAT from human genomic DNA, accomplished through functional complementation of mutant Chinese hamster ovary cells lacking ACAT activity, to initiate progress in understanding the biochemistry of ACAT function (2). The mRNA for this ACAT is expressed in most human tissues and cDNAs with nearly identical ACAT sequences have likewise been found in a variety of tissues from mouse, hamster, and rabbit (3-5).Several functions can be attributed to cholesterol esterification by ACAT. The enzyme appears to modulate the potentially toxic effects of cholesterol in cell membranes. By attaching a fatty acid to the free hydroxyl group of cholesterol, physical properties of the cholesterol molecule are changed and the solubility of esterified cholesterol in the lipids of the cell membrane is limited. Cholesteryl esters accumulate in lipid droplets in the cytoplasm, and maintenance of a balance between the free and esterified forms of cholesterol in a cell is believed to be a component of regulation of cholesterol signaling pathways (6...

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“…'- 3 LDL particle size has been highly correlated with the extent and severity of coronary artery atherosclerosis (CAA). 3 -5 Increased LDL size is characterized by an increase in the number of cholesteryl ester molecules in the core of the particle, with smaller increases in the surface constituents of LDL.…”

mentioning

confidence: 99%

Hepatic ACAT activity in African green monkeys is highly correlated to plasma LDL cholesteryl ester enrichment and coronary artery atherosclerosis.

Carr

Parks

Rudel

1992

Arterioscler Thromb

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130

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Previous studies and this study of African green monkeys show a strong positive correlation between plasma low density lipoprotein (LDL) size and the extent of coronary artery atherosclerosis (CAA). Increased LDL size was principally due to the accumulation of cholesteryl oleate molecules within the particle core, suggesting that many of these cholesteryl esters were of tissue origin, i.e., from the acyl-coenzyme A: cholesterol acyltransferase (ACAT) reaction instead of the lecithin: cholesterol acyltransferase (LCAT) reaction. The current study was conducted to test the hypothesis that ACAT in the liver is the source of the increased numbers of cholesteryl oleate molecules in plasma LDL particles that appear to increase the atherogenic potential of LDL. Monkeys were fed diets rich in fat (lard, safflower oil, or fish oil) and cholesterol for 3-6 years before liver perfusion, ACAT assay, and evaluation of CAA. develop hypercholesterolemia characterized by an increased low density lipoprotein (LDL) concentration and enlargement of LDL particle size.'-3 LDL particle size has been highly correlated with the extent and severity of coronary artery atherosclerosis (CAA).3 -5 Increased LDL size is characterized by an increase in the number of cholesteryl ester molecules in the core of the particle, with smaller increases in the surface constituents of LDL. 16 Since the majority of plasma LDL is believed to arise from the intravascular catabolism of hepatic apoprotein (apo) B100-containing lipoproteins, 2 increased LDL size and cholesteryl ester concentration are the likely result of increased cholesteryl ester synthesis and secretion in apoBlOO lipoproteins by the liver. Indeed, liver perfusion studies in African green monkeys fed high-fat, high-cholesterol diets have demonstrated significant positive correlations between the rate of hepatic cholesterol secretion and both plasma cholesterol concentration and LDL particle size.7 -9 This relation exists even when the type of fat and amount of cholesterol in the diet are altered. These data suggest that mechanisms regulating lipoprotein synthesis and secretion by the liver play a critical role in determining the size and concentration of plasma LDL and, consequently, the development of CAA.Acyl-coenzyme A:cholesterol acyltransferase (ACAT) catalyzes the intracellular formation of cholesteryl ester from fatty acyl-coenzyme A (CoA) and free cholesterol. In the liver, this reaction is undoubtedly responsible for the majority of cholesteryl ester secreted with apoBlOOcontaining lipoproteins. The fatty acid specificity of ACAT has been systematically studied in rats, with oleoyl-CoA being the preferred substrate and other acyl-CoAs being somewhat less efficiently used.

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Dietary ethanol-induced modifications in hyperlipoproteinemia and atherosclerosis in nonhuman primates (Macaca nemestrina).

Cited by 70 publications

References 17 publications

Studies on the production of low density lipoproteins by perfused livers from nonhuman primates. Effect of dietary cholesterol.

Studies on the production of low density lipoproteins by perfused livers from nonhuman primates. Effect of dietary cholesterol.

Identification of a Form of Acyl-CoA:Cholesterol Acyltransferase Specific to Liver and Intestine in Nonhuman Primates

Hepatic ACAT activity in African green monkeys is highly correlated to plasma LDL cholesteryl ester enrichment and coronary artery atherosclerosis.

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