REGULATION OF INTESTINAL LIPID TRANSPORT

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Triacylglycerol (TG) is the most efficient caloric source available to the body and its malabsorption signals disease. Its normal transport from the intestine in chylomicrons is associated with its physiological distribution to targets in the periphery. Non-chylomicron transported dietary lipid is likely to be delivered directly to the liver. Lipid transport from the liver is in VLDL whose metabolic end product is LDL, the major serum cholesterol transporter. This proposal is designed to study mechanisms whereby lipid transport from the intestine via chylomicrons can be modulated and the amount of lipid reaching the liver from the intestine documented. Five areas will be explored. (1) Since phosphatidylcholine (PC) synthesis is of major import in providing the phospholipid surface coat on chylomicrons, the fractional turnover rate and pool size in intestinal mucosa which subserves chylomicron formation will be studied. Both routes by which PC can be synthesized will be investigated because each may be separately regulated. The studies will be performed under conditions in which TG output into the lymph is increased by a factor of two by physiological means. (2) Similar studies will be performed to determine the mucosal precursor pool size and fractional turnover rate for apo-lipoproteins B48 and A1. These apo-lipoproteins are major protein components of the chylomicron surface coat. The absence of apo-B is associated with no chylomicron formation so that its adequate synthesis is crucial to normal chylomicron transport. (3) Studies will be performed to document the transport of lipid that is not transported via the lymph. Since 50% of infused lipid is not transported in the lymph, these alternate pathways are quantitatively important to understanding intestinal lipid transport. The mechanism by which this occurs within the mucosal cell and the route of its transport, presumedly the portal vein, will be investigated. (4) The intracellular distribution of absorbed lipid is important in understanding its transport. Studies will be performed which will enable the intracellular identification of the mucosal chylomicron precursor pool. Additional studies will focus on what induces absorped lipid to pellet under low centrifugal force. (5) New drugs are able to completely inhibit PC synthesis at least in liver. Since the same biochemical pathways are present in intestine, these drugs will be studied to observe their effect on PC synthesis in the intestine and its effect of TG transport.