The long-term goal of this research is to gain a better understanding of the mechanisms and factors regulating the assembly and secretion of chylomicron (CM) and very low density lipoprotein (VLDL) by the small intestine. During the last funding period, we made 3 major observations. First, we demonstrated that the secretion of apolipoprotein B (apo B) into lymph by the small intestine was unaltered by acute feeding of triglyceride (TG). Second, we showed that the stimulation of intestinal synthesis and secretion of apolipoprotein A-IV (apo A-IV) by lipid feeding is related to the formation and secretion of CM. Third, we discovered that apo A-IV is a potent satiety factor. These observations form the basis for the current renewal grant which addresses 2 hypotheses: Part I) The biosynthesis and secretion of apo B, and thus the number of TG-rich particles made by the small intestine, is stimulated in rats fed chronically with a high lipid diet and in genetically obese Zucker (fa/fa rats. Part 20 The stimulation of intestinal apo A-IV synthesis and secretion by fat feeding is dependent on the type and dose of lipid. To test these hypotheses, lymph fistula rats will be used. This is a useful model for studying lipid absorption and apolipoprotein biosynthesis and secretion by the small intestine in conscious rats.
SPECIFIC AIM 1. Chronic feeding of a high fat diet enhances the ability of the small intestine to transport lipid into lymph. We will test the hypothesis that chronic feeding of a high fat diet induces the small intestine to synthesize and secrete more apo B. This, in turn, induces the small intestine to make more TG-rich particles since the amount of apo B per TG-rich particle is constant.
SPECIFIC AIM 2. We will test the hypothesis that genetically obese Zucker (fa/fa) rats can absorb and transport lipid into lymph better than their lean littermates (FA/-) and that this is a result of increased apo B synthesis and transport by their small intestine.
SPECIFIC AIM 3. We will determine the dose-response relationship between the dose of lipid fed and the synthesis and secretion of apo A-IV by the jejunum. We will also compare the A-IV response to lipid feeding in jejunum and in ileum. Lastly, we will determine the effect of the type of fat on apo A-IV response by the jejunum.
SPECIFIC AIM 4. We will determine the molecular mechanisms responsible for the pre-translational and translational regulation of apo A-IV MRNA in the small intestine after L-81 treatment.
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