Effects of dietary fats and cholesterol on liver lipid content and hepatic apolipoprotein A-I, B, and E and LDL receptor mRNA levels in cebus monkeys.

The effects of the long-term administration of the dietary fats coconut oil and corn oil at 31% of calories with or without 0.1% (wt/wt) dietary cholesterol on plasma lipoproteins, apolipoproteins (apo), hepatic lipid content, and hepatic apoA-I, apoB, apoE, and low density lipoprotein (LDL) receptor mRNA abundance were examined in 27 cebus monkeys. Relative to the corn oil-fed animals, no significant differences were noted in any of the parameters of the corn oil plus cholesterol-fed group. In animals fed coconut oil without cholesterol, significantly higher ( P < 0.05) plasma total cholesterol (145%), very low density lipoprotein (VLDL) + LDL (201%) and high density lipoprotein (HDL) (123%) cholesterol, apoA-I (103%), apoB (61%), and liver cholesteryl ester (263%) and triglyceride (325%) levels were noted, with no significant differences in mRNA levels relative to the corn oil only group. In animals fed coconut oil plus cholesterol, all plasma parameters were significantly higher ( P < 0.05). as were hepatic triglyceride (563%) and liver apoA-I (123%) and apoB (87%) mRNA levels relative to the corn oil only group, while hepatic LDL receptor mRNA (-29%) levels were significantly lower ( P < 0.05). Correlation coefficient analyses performed on pooled data demonstrated that liver triglyceride content was positively associated ( P < 0.05) with liver apoA-I and apoB mRNA levels and negatively associated ( P < 0.01) with hepatic LDL receptor mRNA levels. Liver free and esterified cholesterol levels were positively correlated ( P < 0.05) with liver apoE mRNA levels and negatively correlated ( P < 0.025) with liver LDL receptor mRNA levels. Interestingly, while a significant correlation (P< 0.01) was noted between hepatic apoA-I mRNA abundance and plasma apoA-I levels, no such relationship was observed between liver apoB mRNA and plasma apoB levels, suggesting that the hepatic mRNA of apoA-I, but not that of apoB, is a major determinant of._the circulating levels of the respective apolipoprotein. Our data indicate that a diet high in saturated fat and cholesterol may increase the accumulation of triglyceride and cholesterol in the liver, each resulting in the suppression of hepatic LDL receptor mRNA levels. We hypothesize that such elevations in hepatic lipid content differentially alter hepatic apoprotein mRNA levels, with triglyceride increasing hepatic mRNA concentrations for apoA-I and B and cholesterol elevating hepatic apoE mRNA abundance.-Hennessy, L. K., J. Osada, J. M. Ordovas, R. J. Nicolosi, A. F. Stucchi, M. E. Brousseau, and E. J. Schaefer. Effects of dietary fats and cholesterol on liver lipid content and hepatic apolipoprotein A-I, B, and E and LDL receptor mRNA levels in cebus monkeys. J. Lipid Res. 1992. 33: 351360. Supplementary key words saturated fat polyunsaturated fat cholesterol apolipoprotein mRNA LDL receptor mRNA liver lipids nonhuman primates Circulating lipoprotein levels play a significant role in the pathogenesis of coronary artery disease (CAD). Data derived from both laboratory animal experiments and from human epidemiologic studies provide evidence of a positive correlation between elevated low density lipoprotein (LDL) concentrations and CAD risk, while the inverse is true for increased levels of high density lipoproteins (HDL) (1-3). Plasma lipoprotein levels are determined by the interaction of a number of genetic and environmental factors, with diet being of great significance in the latter category. The relevance of dietary fatty acid and cholesterol content with respect to the regulation of plasma lipids is well documented (4-6). Both in the presence and absence of significant dietary cholesterol, saturated fat compared with polyunsaturated fat causes significant increases in LDL cholesterol levels (4, 7) , with chain length being a determinant in the hypercholesterolemic effect of saturates (8-10). The influence of these nutritional factors on HDL cholesterol levels, however, is somewhat more controversial. While it appears conclusive that saturated fatty acids increase HDL cholesterol concentrations ( 5 ) , the evidence concerning Abbreviations: CAD, coronary artery disease: VLDL, very low density lipoproteins; LDL, low density lipoproteins; HDL, high density lipoproteins: IDL, intermediate density lipoproteins. 'To whom correspondence should be addressed at: Lipid Metabolism Laboratory, USDA Human Nutrition Research Center on Aging at Tufts University, 711 Washington Street, Boston, MA 02111. Journal of Lipid Research Volume 33, 1992 351 by gest, on July 0, 2011 w w w .j.org D ow nladed fom polyunsaturates is equivocal. High polyene diets have been reported to lower HDL cholesterol (4, 1 1 , 12), or show no effects (13, 14). As a result of their phylogenetic similarity to humans, their diet responsiveness, and their ability to develop atherosclerosis, nonhuman primates provide an excellent model for studies of diet-induced atherosclerosis. In addition to providing evidence of the involvement of dietary fat and cholesterol in the regulation of the receptor-mediated catabolism of LDI, (15, 16), recent investigations in nonhuman primates have demonstrated that these nutrients may mediate the expression of genes encoding apolipoproteins and the LDL receptor. In studies in African green monkeys, Sorci-Thomas et al. (17) have reported that dietary fat type can differentially alter apoA-I gene expression in a tissue-specific manner, with saturates enhancing and polyunsaturates reducing expression, respectively. This group has further shown that, when fed similar atherogenic diets, cynomolgus monkeys synthesize comparatively less apoA-I than do African green monkeys, the latter being much less susceptible to diet-induced hypercholesterolemia (18). While other studies by this group (19) have failed to demonstrate an influence of such nutrients on hepatic apoB mRNA abundance, alterations in this parameter have been induced by cholesterol feeding in both rabbits (20) and rats (21), suggesting species-specific regulation at the molecular level. Moreover, hepatic apoE gene expression appears to be regulated by dietary saturated fat and cholesterol, as rhesus monkeys fed diets enriched in these nutrients have demonstrated increased synthesis of apoE during liver perfusion studies (22). In baboons, Fox et al. (23) have also reported significant reductions in mRNA for hepatic LDL receptors, consequent to the consumption of diets enriched in saturated fat and cholesterol. In order to further define the mechanisms by which dietary fatty acids and cholesterol affect circulating lipid and apolipoprotein levels, we assessed the relationships between these parameters and hepatic lipid and mRNA content in cebus monkeys fed diets of differing fatty acid composition in the presence or absence of cholesterol. We hypothesized that, relative to a corn oil-enriched diet without cholesterol, a diet high in saturated fat and cholesterol may induce changes at the molecular level by increasing hepatic lipid content, resulting in the differential regulation of apoA-I, B, and E and LDL receptor mRNA levels. into four groups and fed semipurified diets that supplied 31% of calories as fat, either as corn oil (Best Foods, Englewood, NJ) or as coconut oil (Capital City Products, Columbus, OH) with or without 0.1% (wt/wt) dietary cholesterol for S to 10 years, Fatty acid analyses of the two dietary fats have been reported elsewhere (24). As we have previously stated ( l 6), nonhydrogenated coconut oil, rather than butter or animal fat, was used as the saturated fat because it does not contain any cholesterol and is the only Fat capable of elevating plasma cholesterol levels in the absence of dietary cholesterol, at least in this animal model. The experimental protocol was in accordance with the guidelines of the Committee on Animals of the University of Lowell Research Foundation and those of the Committee on Care in Use of Laboratory Animals of the Institute of Laboratory Animal Resources, National Research Council (DHEW publication #85-23,