REGULATION OF INTESTINAL LIPID TRANSPORT

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DESCRIPTION: The movement of triacylglycerol (TG) from the intestinal lumen to the lymph in a chylomicron particle is an important function of the intestinal mucosal cell since on metabolism of the chylomicron to produce a chylomicron remnant, HDL is produced as a product. New evidence suggests that remnant production results in the majority of the HDL particles in the plasma. Since HDL is the reverse cholesterol transport particle, the subject of this proposal, which is directed toward understanding the mechanisms by which absorbed TG is directed toward chylomicron formation rather than going directly to the liver via the portal vein, is clinically important. The movement of TG from its site of synthesis in the endoplasmic reticulum (ER) to the Golgi has been an important but unexplored area of research in how TG transits the enterocyte. Recent cell biological studies in the PI's laboratory provide considerable evidence for a unique vesicular transport mechanism for this. The rapidity of movement of TG between the ER and the Golgi correlates with the ability of the intestine to transport TG into the lymph as chylomicrons. Preliminary data show that apolipoprotein AI is present in the ER but not in the transport vesicle. This leads to proposed experiments to define the mechanism by which apoAI does not associate with the developing chylomicron in the ER, and the role of apoAI in the accretion of TG by the cylomicron in the ER. The proteins responsible for the targeting of chylomicrons to the intestinal Golgi in the TG-transport vesicle, the cytosolic protein responsible for enabling fusion of the TG-transport vesicle with the Golgi, and the docking protein on the Golgi that functions to give intestinal Golgi the required binding specificity, will be determined. Studies will also determine the composition of the vesicles, and will determine the flow of TG and apoB-48 from ER to TG-transport vesicle to Golgi. The investigator has found that the intravenous administration of chylomicrons increases the output of TG into the lymph in lymph fistula rats. The second aim of the application is to examine if this is due to the utilization of phosphatidylcholine (PC) from chylomicron remnants for either TG-transport vesicle membrane or chylomicron surface formation. Newly synthesized PC will also be studied for its preferential utilization for TG-transport vesicle membrane or chylomicron surfaces as compared to ER membrane PC. To determine whether PC or apo-B48 drives the TG transport process, studies will also be done in bile fistula, TG-infused and TG+PC-infused rats, to determine if lymph TG output can be dissociated from lymph apoB-48 output.