Metabolic mechanisms for responses to dietary cholesterol and fat in high and low LDL responding

These studies were conducted to determine how plasma low density lipoprotein (LDL) cholesterol levels respond to dietary cholesterol, fed in increasing amounts with either corn oil or coconut oil diets, in high as compared to low LDL re- sponding baboons; and to determine how apolipoprotein (apo) B transcription levels are modulated in response to dietary lipids. Eight high and eight low LDL responding pedigreed adult baboons, balanced for sire, age, sex, and weight, were challenged for successive 7-week periods with increasing levels of dietary cholesterol combined with either coconut oil or corn oil. At the end of each dietary period, plasma and lipoprotein lipids, apoB, apoA-I, and hepatic mRNA levels for apolipoproteins were measured. As dietary cholesterol increased, plasma choles- terol concentrations (mostly LDL cholesterol) increased in both phenotypes and with both types of fat, but phenotypic differ- ences were greater with coconut oil. There was not a consistent dose-response relationship of plasma or LDL cholesterol levels to increasing intakes of dietary cholesterol. Neither dietary cho- lesterol, type of dietary fat, nor LDL phenotype affected hepatic apoB or apoE mRNA levels. In a second experiment to resolve the inconsistent dose-response to dietary cholesterol, we fed the animals varying levels of dietary cholesterol combined with coconut oil, and separated the challenge periods with interven- ing 12-week chow periods. Plasma and LDL cholesterol and apoB concentrations rose consistently with increasing dietary cholesterol, and the slope of the increase diminished at the higher doses. I The results suggest that genetic differences in the initial response of LDL cholesterol to dietary cholesterol and saturated fatty acids are not due to the differences in hepatic transcription of apoB, and that the preceding dietary intake of cholesterol and saturated fatty acids is a major determinant of the response of plasma lipids and the associated metabolic pro- cesses to a dietary challenge. The response of baboon plasma LDL cholesterol concentrations to dietary cholesterol, when fed with saturated fatty acids, is similar to that of humans.-Kush- waha, R. S., C. A. Reardon, G. S. Getz. D. S. Lewis. K. S. Elevated levels of low density lipoproteins (LDL) and reduced levels of high density lipoproteins (HDL) are as- sociated with atherosclerosis in humans and experimental animals (1-4), and are regulated by both genetic and dietary factors, including dietary cholesterol (5-8). Dietary cholesterol increases LDL concentration, alters HDL size and density, and usually (in high responding animal spe- cies) increases very low (VLDL) and intermediate (IDL) density lipoprotein concentrations (6). Dietary cholesterol combined with saturated fatty acid also increases the con- centrations of HDL-containing apoE in many animals, particularly in dogs (6). High performance liquid chromatographic lipoprotein profiles of selectively bred baboons identified families of baboons with low or high LDL responses to a challenge high cholesterol and high saturated fat (HCHF) diet (9). Comparison of responses of high and low line baboons in- dicated that the phenotypic difference is mainly in the VLDL + LDL cholesterol response to dietary cholesterol (10). To identify the genetic basis of the differences in VLDL + LDL cholesterol responses between high and low lines, it is necessary to determine the metabolic mechanism(s) responsible for the contrasting phenotypes. The present studies were conducted to compare the dose- response relationship of plasma LDL cholesterol levels to dietary cholesterol between high and low LDL responding baboons; and to determine whether the higher plasma apoB concentration in high LDL responding baboons was related to increased apoB transcription in the liver.