Polyunsaturated fats can readily undergo peroxidation to yield lipid hydroperoxides that are potentially toxic to the intestine and other tissues when absorbed from the lumen. Despite previous attempts to study hydroperoxide absorption and its lymphatic transport, the factors that influence these processes are not known, and the metabolic fate of peroxidized lipids in the intestine remains poorly understood. An important aspect that has not been established is the role of glutathione (GSH) in the metabolism of lipid peroxides by the small intestine. Since GSH plays a key role in GSH peroxidase-catalyzed reduction of lipid peroxides, the status of mucosal GSH could significantly alter the metabolic fate of dietary peroxidized lipids. Therefore, the overall objective of this proposal is to characterize the effect of GSH on intestinal handling of luminal lipid hydroperoxides. We hypothesize that alterations in mucosal GSH will markedly affect the metabolism of lipid hydroperoxides at the level of absorption, mucosal degradation, lymphatic transport, and subsequent association with lipoproteins of lymph. To test this hypothesis, we propose the following specific aims: (1) To determine the effect of GSH deficiency on intestinal absorption and lymphatic transport of lipid hydroperoxides. (2) To investigate what effects exogenous GSH supplementation has on these processes. (3) To quantify the products derived from mucosal hydroperoxide metabolism. (4) To characterize and quantify associations of hydroperoxides with specific lipoprotein fractions of lymph. (5) To define the effects of fatty acid composition and fat content on hydroperoxide absorption and transport.
These aims will address three important aspects of intestinal handling of luminal peroxidized lipids: (a) the physiological significance of mucosal and exogenous GSH in hydroperoxide absorption and transport (Aims 1 & 2), (b) the function of GSH in intracellular processing of absorbed hydroperoxides (Aims 3 & 4), and (c) the influence of the type and quantity of luminal fat on hydroperoxide absorption and transport (Aim 5). For the proposed studies, the conscious, lymph fistula rat will be used. This model will allow us to quantify recoveries of lipid hydroperoxides in intestinal lumen, mucosa and lymph under steady-state conditions. The results of these studies will greatly enhance our understanding of the metabolism of dietary lipid hydroperoxides by the small intestine, and of the contributions of GSH and luminal fat to this process. The results should also provide useful information regarding the potential therapeutic benefits of dietary supplementation of GSH.
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