Dietary polyunsaturated fat modifies low-density lipoproteins and reduces atherosclerosis of nonhuman primates with high and low diet responsiveness

Abstract

We tested the hypothesis that an increased content of n-6 polyunsaturated fatty acids (principally linoleic acid) in an atherogenic diet of nonhuman primates would decrease atherosclerosis by modifying the composition and decreasing the concentration of plasma low-density lipoprotein (LDL). A species readily susceptible to diet-induced atherosclerosis (cynomolgus monkey) was compared with a less-susceptible species (African green monkey) with dietary cholesterol concentration and saturated or polyunsaturated fat (40% of energy) as variables. In both species, cholesterol concentrations in whole plasma, LDL, and high-density lipoprotein (HDL) were 20-30% lower when polyunsaturated fat was fed, whereas dietary cholesterol increased LDL cholesterol three- to fourfold. LDL was enriched in cholesteryl oleate when saturated fat and cholesterol were fed. Dietary linoleic acid prevented cholesteryl oleate enrichment and promoted cholesteryl linoleate accumulation in LDL. At the same plasma cholesterol concentration, cynomolgus monkeys had higher LDL cholesterol and lower HDL-cholesterol concentrations than did African green monkeys. LDL particle size was significantly (P < 0.001) larger in the group of cynomolgus monkeys fed polyunsaturated fat but tended to be smaller in African green monkeys fed polyunsaturated fat. Dietary polyunsaturated fat protected against coronary artery atherosclerosis in both species. Thus, LDL particle size, per se, was not atherogenic; instead, coronary artery atherosclerosis and cholesteryl oleate enrichment of LDL were more highly correlated. This outcome suggests that information about LDL composition may be more important for understanding the pathogenesis of atherosclerosis than previously suspected.

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

“…This observation has also been made in several studies of coronary artery atherosclerosis in primates 11,12,18,19 and is reproduced in the aortas of the mice of this study. The n-3 polyunsaturated fat appeared to be more effective than the n-6 polyunsaturated fat, although only 1 level of either polyunsaturated fat was studied here (7.2 energy% of n-6 versus 1.4 energy% of n-3 fatty acids), and therefore, the dose response is not known.…”

“…12,18 We examined the livers of monkeys in isolated liver perfusion studies and found a high correlation between cholesteryl ester accumulation in apoB-containing particles secreted during perfusion and the extent of coronary artery atherosclerosis in the liver donor animals, suggesting that the accumulation of cholesteryl esters in LDL and the associated increase in atherosclerosis might be in response to stimulated hepatic secretion. 36 The stimulation of hepatic cholesteryl ester secretion was apparently due to a stimulation of hepatic acyl coenzyme A:cholesterol acyltransferase by oleic acid.…”

“…Therefore, we have used this mouse as a model to compare atherosclerosis outcomes in response to 5 different dietary fat types containing enrichments in saturated, cis and trans monounsaturated, and n-3 and n-6 polyunsaturated fatty acids, with all groups being compared with a standard commercial mouse diet (control) group. To the extent that dietary fatty acid-induced alterations in LDL cholesteryl ester composition participate in the overall atherogenicity of LDL, as has been hypothesized to be the case on the basis of outcomes in monkeys, 12,18 a mouse model with LDL as the primary lipoprotein may permit the hypothesis to be tested.…”

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

“…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.…”

In vivo activation of leukocyte GPR120/FFAR4 by PUFAs has minimal impact on atherosclerosis in LDL receptor knockout mice

“…Dietary linoleic acid (LA; 18:2 n-6) is cardioprotective in humans, such that a 5% increase in energy intake from LA is associated with a 10% and 13% lower risk of coronary heart disease events and deaths, respectively (17). Nonhuman primates and mice fed diets enriched in LA are protected from atherosclerosis compared with their counterparts fed diets enriched in saturated/monounsaturated fat (22)(23)(24). Concerns that increased n-6 PUFA consumption may result in elevated membrane arachidonic acid (AA; 20:4 n-6), increased cellular inflammation, and atherosclerosis exacerbation lack support in humans (16).…”