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.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
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General Medicine A Subcommittee 2 (GMA)
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University of Tennessee Health Science Center
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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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