Apolipoprotein (apo) A-IV is a protein produced by the intestine which is thought to play a physiological role in cholesterol and lipoprotein metabolism, and may also be a satiety signal and an enterogastrone. However, the factors involved in the control of synthesis and secretion of apo A-IV are unclear. It is known that intestinal A-IV is stimulated by dietary fat, but the mechanisms for this response are poorly understood. The long-term goal of this research is to gain a better understanding of the mechanisms regulating the expression, synthesis and secretion of intestinal apo A-IV. Preliminary studies show that 1) lipid in the ileum produces a signal which appears to act via the vagus nerve to stimulate synthesis of apo A-IV in the jejunum, and 2) this signal may be involved in the integrated response of apo A-IV to a fat meal. These findings form the basis for this proposal. The investigator will address 3 hypotheses: 1) Intestinal lipid-elicited signals from the distal gut stimulate expression and synthesis of apo A-IV in the proximal gut, thus playing an important role in the response of A-IV to dietary fat intake; 2) Peptide tyrosine-tyrosine (PYY) is an endocrine mediator for this effect; and 3) PYY's effect on intestinal apo A-IV is vagally mediated. To test these hypotheses, Thiry-Vella fistula rats will be used. The investigator has established this as a useful model for studying the neurohormonal control of intestinal apo A-IV in rats.
Specific aim 1 is to test the hypothesis that ileal delivery of lipid, independent of the presence of jejunal lipid, is sufficient to stimulate expression and synthesis of jejunal apo A-IV.
Specific aim 2 is to test the hypothesis that the effect of lipid in the distal gut on jejunal apo A-IV expression and synthesis depends upon chylomicron assembly and transport.
In specific aim 3, the investigator will test the hypothesis that PYY is a physiological mediator of the effect of distal gut lipid on jejunal apo A-IV expression, synthesis and secretion.
Specific aim 4 is to test the hypotheses that vagal innervation is required for 1) the effect of ileal lipid on apo A-IV, and 2) such innervation is also required for the effect of PYY on apo A-IV expression, synthesis and secretion. This research is the first to examine the relationship between the brain-gut axis and intestinal apolipoprotein A-IV. It will greatly enhance our understanding of the control of this important protein.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
First Independent Research Support & Transition (FIRST) Awards (R29)
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General Medicine A Subcommittee 2 (GMA)
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Louisiana State University Hsc Shreveport
Schools of Medicine
United States
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Spaulding, Heather L; Saijo, Fumito; Turnage, Richard H et al. (2006) Apolipoprotein A-IV attenuates oxidant-induced apoptosis in mitotic competent, undifferentiated cells by modulating intracellular glutathione redox balance. Am J Physiol Cell Physiol 290:C95-C103
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