The goal of this research proposal is to give us a better understanding of the mechanism of formation and transport of chylomicrons (CM) and very low density lipoproteins (VLDL) by the rat small intestine. To achieve this goal, we will utilize this unique tool, the hydrophobic surfactant, Pluronic L-81 (L-81). Studies by the principal investigator have demonstrated that intraduodenal infusion of triolein or cholesterol plus L-81 results in markedly reduced lymphatic lipid output. L-81 affects exclusively the formation and transport of CM, but not that of the VLDL sized particles. Furthermore, L-81 does not affect lymphatic lipid output when egg lecithin (PC) is infused. First we will measure the secretion of CM and VLDL into lymph during intraduodenal infusion of egg PC with and without L-81 added. We will also study whether inhibition of lymphatic transport of TG caused by L-81 is reversed by duodenal infusion of PC. Using TG and PC containing radioactively labeled fatty acid (FA), we will investigate the utilization of the FA derived from luminal TG and PC in the formation and secretion of the CM and VLDL by the small intestine. We will study the synthesis of apolipoprotein B by the small intestine in the presence and absence of L-81. Furthermore, we will study whether the stimulation of VLDL production by enterocytes after the intraduodenal infusion of egg PC is caused by factors other than its FA composition. Lastly, we will investigate the subcellular site of the defect in the intracellular assembly and secretion of CM caused by L-81. The long-term objective of this research is to better understand the mechanism and the factors regulating the formation and secretion of CM and VLDL by the small intestine. Through this knowledge we may be able to modulate the amount of lipid entering the plasma from the small intestine in patients suffering from obesity and hyperlipidemia.
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