The overall objective of this research is to investigate the effects of nutrition intervention on low density lipoprotein (LDL) metabolism using a nonhuman primate model (Macaca fascicularis). The dietary treatment will include three levels of fat (40, 30 and 20% of calories), with fat types composed of P/S ratios of 0.45, 1.0 and 2.0 and cholesterol intakes of 100 and 240 mg/1000 kcals to be fed sequentially at six-month intervals. Recent observations in this monkey model indicate that animals maintained on the 30% calories as fat, P/S ratio of 1.0 and the equivalent of 120mg cholesterol/1000 kcals have lower LDL cholesterol (-32%), higher high density lipoprotein (HDL) cholesterol (+16%) and higher apo A-I levels (+33%) than monkeys maintained on the higher fat levels (42% kcals as fat). On the otherhand, monkeys on the lower fat level and higher P/S ratio (1.0) have higher apo B levels than monkeys fed the diet with an equivalent P/S ratio but the higher fat level (42% kcals). This not only emphasizes the importance of investigating dietary fat level/fat type interactions but also suggests that diet effects on LDL cholesterol and apo B may be dissimilar. Thus, in this sensitive animal model, we are proposing to utilize biochemical and molecular biology approaches to investigate diet determinants of LDL metabolism by (a) measuring plasma lipids and apoproteins (b) assessing receptor-dependent and receptor-independent pathways of LDL metabolism in vivo. (c) measuring levels of hepatic mRNA for apo B to document the relationship of apo B mRNA to parameters of LDL metabolism defined in vivo and in the in vitro isolated liver perfusion system (d) measuring levels of hepatic LDL receptor mRNA and correlating them with receptor dependent LDL catabolic rates and (e) characterizing the LDL and/or LDL-""""""""like"""""""" particles formed as well as the apo B synthetic rates using an in vitro liver perfusion system.
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