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.
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