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.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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General Medicine A Subcommittee 2 (GMA)
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May, Michael K
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University of Tennessee Health Science Center
Internal Medicine/Medicine
Schools of Medicine
United States
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Siddiqi, Shahzad; Saleem, Umair; Abumrad, Nada A et al. (2010) A novel multiprotein complex is required to generate the prechylomicron transport vesicle from intestinal ER. J Lipid Res 51:1918-28
Siddiqi, Shahzad; Siddiqi, Shadab A; Mansbach 2nd, Charles M (2010) Sec24C is required for docking the prechylomicron transport vesicle with the Golgi. J Lipid Res 51:1093-100
Mansbach, Charles M; Siddiqi, Shadab A (2010) The biogenesis of chylomicrons. Annu Rev Physiol 72:315-33
Siddiqi, Shadab A; Mansbach 2nd, Charles M (2008) PKC zeta-mediated phosphorylation controls budding of the pre-chylomicron transport vesicle. J Cell Sci 121:2327-38
Mansbach 2nd, Charles M; Gorelick, Fred (2007) Development and physiological regulation of intestinal lipid absorption. II. Dietary lipid absorption, complex lipid synthesis, and the intracellular packaging and secretion of chylomicrons. Am J Physiol Gastrointest Liver Physiol 293:G645-50
Neeli, Indira; Siddiqi, Shadab A; Siddiqi, Shahzad et al. (2007) Liver fatty acid-binding protein initiates budding of pre-chylomicron transport vesicles from intestinal endoplasmic reticulum. J Biol Chem 282:17974-84
Siddiqi, Shadab A; Mahan, James; Siddiqi, Shahzad et al. (2006) Vesicle-associated membrane protein 7 is expressed in intestinal ER. J Cell Sci 119:943-50
Lu, Song; Yao, Ying; Cheng, Xiangying et al. (2006) Overexpression of apolipoprotein A-IV enhances lipid secretion in IPEC-1 cells by increasing chylomicron size. J Biol Chem 281:3473-83
Siddiqi, Shadab A; Siddiqi, Shahzad; Mahan, James et al. (2006) The identification of a novel endoplasmic reticulum to Golgi SNARE complex used by the prechylomicron transport vesicle. J Biol Chem 281:20974-82
Maroney, S A; Cunningham, A C; Ferrel, J et al. (2006) A GPI-anchored co-receptor for tissue factor pathway inhibitor controls its intracellular trafficking and cell surface expression. J Thromb Haemost 4:1114-24

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