A neonatal swine model will be used to study the ontogeny of intestinal lipoprotein (Lp) and apolipoprotein (apoLp) formation, secretion and metabolism. Little is known of these processes in the developing mammal. Preliminary studies show: 1) neonatal piglets can be maintained for prolonged periods with mesenteric lymphatic, duodenal, and vascular cannulae; 2) plasma Lps and patterns of intestinal lymph Lp secretion during lipid absorption are similar to mature mammals including humans; and 3) intestinal lymph and plasma apoLp patterns are similar to mature humans including the presence of apo B-100, B-48, A-IV, E, A-I, and C. Apo AI has 5 isoforms with the more acidic isoform 3 predominating in plasma high density Lp (HDL). Apo B-100 constitutes all of apo B in plasma very low density Lp (VLDL) and low density Lp (LDL), but both apo B-100 and B-48 are present in lymph chylomicrons (CM) and VLDL, a pattern not found in mature mammals. Specific objectives: Phase I: 1) determine developmental patterns of intestinal LP and apoLp secretion in newborn, suckling, and weanling piglets with detailed quantitative analyses, including Lp isolation by density gradient ultracentrifugation and apoLp quantitation by immunoassay, 2) determine the origin of lymph Lps (CM, VLDL, LDL, and HDL) lipid using duodenal infusion of 3H-fatty acid and 14C-cholesterol; and 3) establish the composition and N-terminal sequence of piglet lymph and plasma apo A-I isoforms 1 and 3 to establish homology with human proapo A-I and mature apo A-I. Phase II: Determine developmental patterns of apoLp synthesis by liver and intestine and their contribution to lymph and plasma Lp apoLps using simultaneous duodenal infusion of 3H-leucine and portal infusion of 14C-leucine with particular attention to origins of lymph Lp apo B-100. These studies will provide information regarding the ontogeny of intestinal Lp synthesis in an in vivo model similar in many ways to the human infant. More importantly, these studies should stimulate future investigations which address how to provide dietary lipid to the developing GI tract to ensure efficient production and metabolism of intestinal Lps.
NIH ExPorter
NIH ExPorter