Apolipoprotein are surface components of lipoprotein particles and serve essential functions in the secretion, metabolism, and receptor-mediated uptake of thee particles. Delineation of the factors that regulate apolipoprotein gene expression in the small intestine of the developing mammal has been difficult because of the simultaneous interaction of several potential regulatory factors and the lack of a suitable animal model. The elucidation of these regulatory mechanisms is essential because of the importance of these proteins in lipoprotein biogenesis and metabolism in the neonate. An in vitro neonatal swine model has been developed which offers the advantages of ease of manipulation and significant homology to the human with regard to lipoprotein metabolism and timing of gastrointestinal maturation. Techniques have been developed to allow study of apolipoprotein expression at the pre-, co-, and post-transnational levels. Studies to date have identified distinct patterns of apo B, A-I, and A-IV expression by dietary and biliary lipid absorption in the intact animal in vivo and by epidermal growth factor, insulin, and hydrocortisone in developmental expression defined. Intestinal expression of apo C-II mRNA is limited to the neonatal jejunum and appears to be highly regulated by lipid absorption. A novel cell line, IPEC-1, derived from the small intestine of an unsuckled newborn piglet, has been characterized with regard to apolipoprotein basolateral membrane secretion of lipoproteins when grown on collagen-coated filters. These cells also exhibit increased secretion of apo B, A-I, and A-IV in response to incubation with fatty acid. Furthermore, these cells absorb free fatty acid, esterify it into intracellular triglyceride, cholesteryl ester, and phospholipid, and secrete lipoproteins containing these lipids. The overall aim of this proposal is to further define the effects of dietary lipid and the hormonal milieu on apolipoprotein gene expression in the small intestine of the neonatal mammal. An integrated approach using intact animals and the IPEC-1 intestinal cell line will achieve the following: 1) Determine whether changes in enterocyte apolipoprotein hormone treatment are accompanied by coordinate changes in lipoprotein composition and secretion in cultured IPEC-1 cells. 2) Determine the effects of feeding short- (24 hours) and long-term (1 week) diets of varying fat composition (saturated versus polyunsaturated, medium versus long chain length) with and without cholesterol on intestinal and hepatic apolipoprotein gene expression and plasma apolipoprotein and lipoprotein profiles using the in vivo newborn pig model. This information should ultimately guide the optimal provision of dietary lipid to the neonate with particular relevance to the lipid composition of infant formulas.
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