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

Abstract

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.

Childhood consumption of dietary polyunsaturated fat lowers risk for coronary artery atherosclerosis in African green monkeys.

“…20 These dietary polyunsaturated fatrelated changes in the risk profiles of young animals were consistent overall with a decreased risk for atherosclerotic CHD because they mirrored those in adult animals fed these same diets in which less atherosclerosis was found. 48 When atherosclerosis evaluations were made in the young animals of this study, less extensive and severe coronary artery atherosclerosis was found in the animals fed polyunsaturated fat. 49 Therefore, the results in this primate model show a benefit of early intervention with dietary polyunsaturated fat against coronary artery atherosclerosis development.…”

Dietary Monounsaturated Fatty Acids Promote Aortic Atherosclerosis in LDL Receptor–Null, Human ApoB100–Overexpressing Transgenic Mice

“…36 The stimulation of hepatic cholesteryl ester secretion was apparently due to a stimulation of hepatic acyl coenzyme A:cholesterol acyltransferase by oleic acid. 37,38 In the mice of these studies, enrichment of LDL with cholesteryl oleate was most pronounced in the cis mono and sat groups, although the lipid milieu in the core of the LDL particles of these mice was quite different from that found in monkeys and humans. A high percentage of triacylglycerol was found in the mouse LDL (Table 4), and significant quantities of cholesteryl arachidonate (and n-3 fatty acid cholesteryl esters in the n-3 poly group) were also found (Table 5).…”

Functional Expression of a cDNA to Human Acyl-coenzyme A:Cholesterol Acyltransferase in Yeast

“…The predominant mammalian hepatic sterol ester which reflects ACAT activity is cholesteryl oleate, but again this may be due to normally low concentrations of the essential 18:2 fatty acid or to alternate metabolism. In this regard, when a diet rich in linoleate was fed to African Green monkeys, the amount of hepatic cholesteryl linoleate increased by 3.3-fold (35).…”