Serum Fatty-Acid Patterns in Coronary-Artery Disease

Lawrie, T. D. V.; McAlpine, Stuart G.; Rifkind, Basil M.; Robinson, J.; Alice, Huertas; McMillan, Beth

doi:10.1016/s0140-6736(61)90003-4

Cited by 21 publications

(7 citation statements)

References 6 publications

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“…Increased amounts of cholesteryl oleate in plasma LDL mean decreased amounts of cholesteryl linoleate (10,37), since these are the two major cholesteryl esters in plasma. Several studies have showed an inverse relationship between the percentage of cholesteryl linoleate in plasma and the complications of atherosclerosis in human patients (9)(10)(11)(12)(13)(38)(39)(40)(41). In this context, a curious situation has occurred where some investigators have measured an increase in the percentage of cholesteryl oleate in LDL (and a decrease in the percentage of cholesteryl linoleate) when diets rich in monounsaturated fat were fed and, at the same time, have recommended diets rich in oleic acid to protect against heart disease because in the test tube, oleate-rich LDL oxidize less well upon incubation with copper (37).…”

Section: Discussionmentioning

confidence: 99%

“…One possible reason for this outcome could be that the dietary monounsaturated fatty acid-induced lipoprotein particle enrichment in cholesteryl oleate (7,8) may be more important than previously suspected, and sufficient to overcome the beneficial antiatherogenic change in LDL to HDL cholesterol ratio. Earlier studies in CHD patients suggested that the percentage of cholesteryl linoleate in plasma lipoproteins was inversely correlated to clinical outcome (9)(10)(11)(12)(13). Such findings suggest that the lack of protection by monounsaturated fatty acids against coronary artery atherosclerosis, as described in African green monkeys (1), may indeed be pertinent for humans, i.e., the shift in LDL cholesteryl ester composition may be an important atherogenic factor that should be considered along with LDL and HDL cholesterol levels.…”

Section: Introductionmentioning

confidence: 95%

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Hepatic origin of cholesteryl oleate in coronary artery atherosclerosis in African green monkeys. Enrichment by dietary monounsaturated fat.

Rudel¹,

Haines²,

Sawyer³

et al. 1997

J. Clin. Invest.

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Relationships among plasma lipoprotein cholesterol, cholesterol secretion by the isolated, perfused liver, and coronary artery atherosclerosis were examined in African green monkeys fed diets containing cholesterol and 35% of calories as fat enriched in polyunsaturated, monounsaturated, or saturated fatty acids. The livers of animals fed monounsaturated fat had significantly higher cholesteryl ester concentrations (8.5 mg/g wet wt) than the livers of the other diet groups (3.65 and 3.37 mg/g wet wt for saturated and polyunsaturated fat groups, respectively) and this concentration was highly correlated with plasma cholesterol and apoB concentrations in each diet group. Cholesteryl oleate was 58 and 74.5% of the liver cholesteryl ester in the saturated and monounsaturated fat groups. In each diet group, perfusate cholesteryl ester accumulation rate was highly correlated to liver and plasma cholesterol concentrations, and to plasma LDL cholesteryl ester content. Cholesteryl oleate was 48 and 67% of the cholesteryl esters that accumulated in perfusate in the saturated and monounsaturated fat animals, and this percentage was very highly correlated ( r ϭ Ϫ 0.9) with plasma apoB concentration. Finally, in these two diet groups, liver perfusate cholesteryl ester accumulation rate was well correlated ( r Ն 0.8) to coronary artery cholesteryl ester concentration, a measure of the extent of coronary artery atherosclerosis that occurred over the five years of diet induction in these animals. These data define an important role for the liver in the cholesteryl oleate enrichment of the plasma lipoproteins in the saturated and monounsaturated fat groups, and demonstrate strong relationships among hepatic cholesteryl ester concentration, cholesteryl ester secretion, and LDL particle cholesteryl ester content. The high correlation between liver cholesteryl ester secretion and coronary artery atherosclerosis provides the first direct demonstration of the high degree of importance of hepatic cholesteryl ester secretion in the development of this disease process.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 95%

Hepatic origin of cholesteryl oleate in coronary artery atherosclerosis in African green monkeys. Enrichment by dietary monounsaturated fat.

Rudel¹,

Haines²,

Sawyer³

et al. 1997

J. Clin. Invest.

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“…23 In addition, several epidemiologic studies have shown that larger LDLs are risk factors for coronary heart disease in humans, [27][28][29][30] and several publications have shown that a higher proportion of cholesteryl linoleate among plasma cholesteryl esters is associated with a reduced incidence of complications from coronary heart disease. [31][32][33][34] Cholesteryl linoleate is typically derived from esterification of cholesterol by the plasma enzyme lecithin:cholesterol acyltransferase (LCAT), whereas the primary cholesteryl ester products of ACAT2 are cholesteryl oleate and cholesteryl palmitate. These observations suggest that coronary heart disease patients compared with healthy controls had lower proportions of LCAT-derived cholesteryl linoleate and, by difference, higher proportions of ACAT2-derived cholesteryl ester.…”

Section: Cellular Functionmentioning

confidence: 99%

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

Rudel

Lee

Parini

2005

ATVB

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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.

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“…In humans, the percentage of cholesteryl linoleate was lower in coronary heart disease patients (5)(6)(7)(8). The percentage of lipoprotein cholesteryl oleate and the rate of hepatic cholesteryl oleate secretion were positively related to the extent of atherosclerosis in monkeys (9,10).…”

mentioning

confidence: 94%

ACAT2 contributes cholesteryl esters to newly secreted VLDL, whereas LCAT adds cholesteryl ester to LDL in mice

Lee

Shah

Sawyer

et al. 2005

Journal of Lipid Research

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The relative contributions of ACAT2 and LCAT to the cholesteryl ester (CE) content of VLDL and LDL were measured. ACAT2 deficiency led to a significant decrease in the percentage of CE (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%). Interestingly, the absence of ACAT2 had no apparent effect on the percentage CE in LDL, whereas LCAT deficiency significantly decreased the CE percentage (38.6 ؎ 4.0% vs. 54.6 ؎ 1.9%) and significantly increased the phospholipid percentage (11.2 ؎ 0.9% vs. 19.3 ؎ 0.1%) of LDL. When both LCAT and ACAT2 were deficient, VLDL composition was similar to VLDL of the ACAT2-deficient mouse, whereas LDL was depleted in core lipids and enriched in surface lipids, appearing discoidal when observed by electron microscopy. We conclude that ACAT2 is important in the synthesis of VLDL CE, whereas LCAT is important in remodeling VLDL to LDL. Liver perfusions were performed, and perfusate apolipoprotein B accumulation rates in ACAT2-deficient mice were not significantly different from those of controls; perfusate VLDL CE decreased from 8.0 ؎ 0.8% in controls to 0 ؎ 0.7% in ACAT2-deficient mice. In conclusion, our data establish that ACAT2 provides core CE of newly secreted VLDL, whereas LCAT adds CE during LDL particle formation. -Lee, R. G., R. Shah, J. K. Sawyer, R. L. Hamilton, J. S. Parks, and L. L. Rudel. ACAT2 contributes cholesteryl esters to newly secreted VLDL, whereas LCAT adds cholesteryl ester to LDL in mice. Abundant evidence in humans demonstrates that increased plasma concentrations of cholesterol in LDL and in VLDL are positively correlated with the development of atherosclerosis (1). A similar relationship between apolipoprotein B (apoB)-containing lipoprotein cholesterol and atherosclerosis has also been observed in studies carried out in LDL receptor-deficient (LDLr Ϫ / Ϫ ) mice (2). Typically, more than 70% of the cholesterol in LDL and VLDL is esterified. Therefore, the two enzymes responsible for the synthesis of plasma lipoprotein cholesteryl esters (CEs), LCAT and ACAT2, (3) are important determinants of both VLDL and LDL cholesterol concentrations and the subsequent development of atherosclerosis.Several studies have provided evidence that the types of CEs that predominate in plasma contribute to the relative degree of atherogenicity (4). In humans, the percentage of cholesteryl linoleate was lower in coronary heart disease patients (5-8). The percentage of lipoprotein cholesteryl oleate and the rate of hepatic cholesteryl oleate secretion were positively related to the extent of atherosclerosis in monkeys (9, 10). A deficiency in plasma LCAT in mice resulted in higher percentages of saturated and monounsaturated CEs and more atherosclerosis (3,11,12). Therefore, polyunsaturated fatty acid containing CEs derived from LCAT are associated with decreased atherosclerosis (11), whereas saturated and monounsaturated CEs derived predominantly from ACAT2 (10) are associated with increas...

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Serum Fatty-Acid Patterns in Coronary-Artery Disease

Cited by 21 publications

References 6 publications

Hepatic origin of cholesteryl oleate in coronary artery atherosclerosis in African green monkeys. Enrichment by dietary monounsaturated fat.

Hepatic origin of cholesteryl oleate in coronary artery atherosclerosis in African green monkeys. Enrichment by dietary monounsaturated fat.

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

ACAT2 contributes cholesteryl esters to newly secreted VLDL, whereas LCAT adds cholesteryl ester to LDL in mice

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