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

Rudel, Lawrence L.; Haines, J; Sawyer, Janet K.; Shah, Ramesh; Wilson, Martha D.; Carr, Timothy P.

doi:10.1172/jci119524

Cited by 75 publications

(72 citation statements)

References 46 publications

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“…Previous studies in non-human primates have documented a strong correlation between hepatic CE content and hepatic CE secretion rate (22) and LDL particle size (23), both of which are highly correlated with coronary artery atherosclerosis (22,24,25). To determine whether LCAT deficiency, which resulted in increased aortic cholesterol deposition, also resulted in increased hepatic cholesterol deposition, we quantified EC and FC in the livers of the study animals ( …”

Section: Resultsmentioning

confidence: 99%

“…However, the compositional data in Table III argue against this interpretation because there is no observable increase in the proportion of FC and PL in the plasma apoB lipoproteins. Our previous studies in non-human primates have shown a strong correlation between hepatic CE content and the concentration of VLDL CE in recirculating liver perfusate, suggesting that hepatic CE storage pools are coupled to VLDL CE secretion (22,23). However, the amount of hepatic CE was similar for both apoEϪ/Ϫ and apoEϪ/Ϫ LCATϪ/Ϫ mice (Fig.…”

Section: Discussionmentioning

confidence: 95%

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Lecithin:Cholesterol Acyltransferase Deficiency Increases Atherosclerosis in the Low Density Lipoprotein Receptor and Apolipoprotein E Knockout Mice

Furbee

Sawyer

Parks

2002

Journal of Biological Chemistry

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The purpose of the present study was to test the hypothesis that lecithin:cholesterol acyltransferase (LCAT) deficiency would accelerate atherosclerosis development in low density lipoprotein (LDL) receptor (LDLr؊/؊) and apoE (apoE؊/؊) knockout mice. After 16 weeks of atherogenic diet (0.1% cholesterol, 10% calories from palm oil) consumption, LDLr؊/؊ LCAT؊/؊ double knockout mice, compared with LDLr؊/؊ mice, had similar plasma concentrations of free (FC), esterified (EC), and apoB lipoprotein cholesterol, increased plasma concentrations of phospholipid and triglyceride, decreased HDL cholesterol, and 2-fold more aortic FC (142 ؎ 28 versus 61 ؎ 20 mg/g protein) and EC (102 ؎ 27 versus 61 ؎ 27 mg/g). ApoE؊/؊ LCAT؊/؊ mice fed the atherogenic diet, compared with apoE؊/؊ mice, had higher concentrations of plasma FC, EC, apoB lipoprotein cholesterol, and phospholipid, and significantly more aortic FC (149 ؎ 62 versus 109 ؎ 33 mg/g) and EC (101 ؎ 23 versus 69 ؎ 20 mg/g) than did the apoE؊/؊ mice. LCAT deficiency resulted in a 12-fold increase in the ratio of saturated ؉ monounsaturated to polyunsaturated cholesteryl esters in apoB lipoproteins in LDLr؊/؊ mice and a 3-fold increase in the apoE؊/؊ mice compared with their counterparts with active LCAT. We conclude that LCAT deficiency in LDLr؊/؊ and apoE؊/؊ mice fed an atherogenic diet resulted in increased aortic cholesterol deposition, likely due to a reduction in plasma HDL, an increased saturation of cholesteryl esters in apoB lipoproteins and, in the apoE؊/؊ background, an increased plasma concentration of apoB lipoproteins.Lecithin:cholesterol acyltransferase (LCAT, 1 EC 2.3.1.43) is a 65-kilodalton glycoprotein that is responsible for the esterification of cholesterol in plasma lipoproteins (1, 2). LCAT catalyzes a two-step reaction that hydrolyzes the sn-2 fatty acid of phospholipid, followed by a transacylation step that transfers the fatty acid to the 3␤-hydroxyl group of cholesterol, generating cholesteryl ester and lysolecithin. LCAT is activated by apolipoprotein A-I, which is the major apolipoprotein on HDL particles (3). The LCAT enzyme is important in the process of reverse cholesterol transport, which involves the movement of cholesterol from peripheral tissues back to the liver for excretion and is critical for the maintenance of normal concentration, size, and shape of plasma lipoproteins (1, 4).There are two types of LCAT deficiency in the human population, familial LCAT deficiency (FLD) and fish eye disease (FED). FLD patients are characterized by a complete lack of plasma LCAT activity, corneal opacification, anemia, proteinurea, and kidney dysfunction that can lead to renal failure (5, 6). These patients have decreased plasma total and esterified cholesterol, HDL cholesterol, apoA-I, and apoA-II concentrations and increased plasma concentrations of triglyceride, phospholipid, free cholesterol, and VLDL cholesterol. FED is characterized by a partial LCAT deficiency in which patients have corneal opacification, but no anemia or renal disease. Lipid a...

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 95%

Lecithin:Cholesterol Acyltransferase Deficiency Increases Atherosclerosis in the Low Density Lipoprotein Receptor and Apolipoprotein E Knockout Mice

Furbee

Sawyer

Parks

2002

Journal of Biological Chemistry

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“…Rudel and colleagues (25,26) have recently used two animal models to compare the effects of various dietary fats on atherosclerosis. In their first study they fed adult male African green monkeys for 5 years with experimental diets containing 35% of calories as fat enriched in palm oil (SFA), oleic acid-enriched safflower oil (MUFA), or safflower oil (PUFA) and Ϸ0.4% (wt͞wt) cholesterol.…”

Section: Discussionmentioning

confidence: 99%

Compared with saturated fatty acids, dietary monounsaturated fatty acids and carbohydrates increase atherosclerosis and VLDL cholesterol levels in LDL receptor-deficient, but not apolipoprotein E-deficient, mice

Merkel

Vélez-Carrasco

Hudgins

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

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Heart-healthy dietary recommendations include decreasing the intake of saturated fatty acids (SFA). However, the relative benefit of replacing SFA with monounsaturated fatty acids (MUFA), polyunsaturated fatty acids (PUFA), or carbohydrates (CARB) is still being debated. We have used two mouse models of atherosclerosis, low density lipoprotein receptor-deficient (LDLRKO) and apolipoprotein E-deficient (apoEKO) mice to measure the effects of four isocaloric diets enriched with either SFA, MUFA, PUFA, or CARB on atherosclerotic lesion area and lipoprotein levels. In LDLRKO mice, compared with the SFA diet, the MUFA and CARB diets significantly increased atherosclerosis in both sexes, but the PUFA diet had no effect. The MUFA and CARB diets also increased very low density lipoproteincholesterol (VLDL-C) and LDL-cholesterol (LDL-C) in males and VLDL-C levels in females. Analysis of data from LDLRKO mice on all diets showed that atherosclerotic lesion area correlated positively with VLDL-C levels (males: r ‫؍‬ 0.47, P < 0.005; females: r ‫؍‬ 0.52, P < 0.001). In contrast, in apoEKO mice there were no significant dietary effects on atherosclerosis in either sex. Compared with the SFA diet, the CARB diet significantly decreased VLDL-C in males and the MUFA, PUFA, and CARB diets decreased VLDL-C and the CARB diet decreased LDL-C in females. In summary, in LDLRKO mice the replacement of dietary SFA by either MUFA or CARB causes a proportionate increase in both atherosclerotic lesion area and VLDL-C. There were no significant dietary effects on atherosclerotic lesion area in apoEKO mice. These results are surprising and suggest that, depending on the underlying genotype, dietary MUFA and CARB can actually increase atherosclerosis susceptibility, probably by raising VLDL-C levels through a non-LDL receptor, apoE-dependent pathway.

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“…Samples were immediately frozen in liquid nitrogen and stored at Ϫ80°C until analyzed. At the end of an atherosclerosis progression period of 3 years in cynomolgus monkeys and 5 years in green monkeys, during which the high cholesterol diet was fed, livers were removed from the animals, and recirculating perfusion was performed as described previously (10,11).…”

Section: Methodsmentioning

confidence: 99%

“…Instead, cholesterol esterification enzymes are candidate sites for regulation. We have shown that when atherogenic diets are fed to primates, the extent of hepatic cholesteryl ester secretion in response to dietary fatty acids is highly correlated to the extent of CAA (10). Hepatic cholesteryl ester secretion in apoB-containing lipoproteins in primates is facilitated by hepatic acyl-coenzyme A:cholesterol acyltransferase (ACAT) (11), and the form of ACAT enzyme present in the hepatocyte is ACAT2 (12,13).…”

mentioning

confidence: 99%

Primates Highly Responsive to Dietary Cholesterol Up-regulate Hepatic ACAT2, and Less Responsive Primates Do Not

Rudel

Davis

Sawyer

et al. 2002

Journal of Biological Chemistry

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The role of liver acyl-CoA:cholesterol acyltransferase 2 (ACAT2), earlier shown to be the principal ACAT enzyme within primate hepatocytes, as a regulator of the hypercholesterolemia induced by dietary cholesterol was studied. At the end of low and high cholesterol diet periods, liver biopsies were taken from cynomolgus monkeys, a species highly responsive to dietary cholesterol, and less responsive African green monkeys. Liver cholesterol and cholesteryl ester concentrations were highest in cynomolgus monkeys fed cholesterol, despite the fact that in order to induce equivalent hypercholesterolemia, dietary cholesterol levels were 50% lower than was fed to green monkeys. Hepatic cholesteryl oleate secretion rate, measured during liver perfusion as an indicator of ACAT activity, was significantly higher in cynomolgus monkeys. Liver microsomal ACAT activity was 2-3-fold higher in cynomolgus monkeys than in green monkeys. The responses of ACAT2 were compared with those of ACAT1 that is found primarily in Kupffer cells. ACAT2 protein mass was significantly correlated to microsomal total ACAT activity in both species; ACAT1 mass was less well correlated. Dietary cholesterol induced a significant 3-fold increase of ACAT2 protein mass in cynomolgus monkeys, a much greater increase than was found for mRNA abundance; neither ACAT2 mRNA nor protein was diet-responsive in green monkeys. In cynomolgus monkeys but not in green monkeys, liver free cholesterol concentrations were elevated when cholesterol was fed and were correlated with ACAT2 protein levels. The data suggest a mechanism whereby the elevation of hepatic free cholesterol concentrations by dietary cholesterol, seen only in cynomolgus monkeys, resulted in higher ACAT2 protein levels in hepatocytes, either through increased production or stabilization of the protein. Regulation of ACAT2 gene transcription was not a factor.

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

Cited by 75 publications

References 46 publications

Lecithin:Cholesterol Acyltransferase Deficiency Increases Atherosclerosis in the Low Density Lipoprotein Receptor and Apolipoprotein E Knockout Mice

Lecithin:Cholesterol Acyltransferase Deficiency Increases Atherosclerosis in the Low Density Lipoprotein Receptor and Apolipoprotein E Knockout Mice

Compared with saturated fatty acids, dietary monounsaturated fatty acids and carbohydrates increase atherosclerosis and VLDL cholesterol levels in LDL receptor-deficient, but not apolipoprotein E-deficient, mice

Primates Highly Responsive to Dietary Cholesterol Up-regulate Hepatic ACAT2, and Less Responsive Primates Do Not

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