The transfer of lipids, and particularly that of phospholipids to and from HDL, mediated by plasma transfer proteins is important for lipoprotein metabolism but the mechanisms of these processes are poorly understood. The objectives of this proposal are to address several broad questions related to the activities of lipid transfer proteins (LTPs) in human plasma. The primary emphasis will be on understanding the mechanism of LTP-2 transfer of phospholipids and the effects of this activity on the remodelling of HDL. There are 5 Specific Aims. One is to determine the molecular mechanisms by which plasma lipid transfer proteins transport lipids between lipid surfaces that are in contact with the plasma compartment. The second is to identify the structural and compositional determinants of plasma lipoproteins that regulate lipid transfer activity. A third objective is to identify the changes in lipid composition and structure that are mediated by lipid transfer proteins and to identify conditions under which phospholipid transfer might enhance neutral lipid transfer. Fourthly, using a combination of photo-affinity labeling and site-directed mutagenesis, the ligand-binding and surface-associating sites of the two major lipid transfer proteins of human plasma will be identified. Finally, the investigators will reconstitute the activities that remodel HDL using the appropriate combinations and concentrations of LTP-2, lecithin-cholesterol acyltransferase (LCAT), LTP-1, hepatic lipase, very low density lipoproteins (VLDL) and lipoprotein lipase. Successful completion of these aims will aid in the understanding of how these factors are altered in abnormal lipid metabolism. This project involves lipid synthesis, lipoprotein isolation and reassembly, kinetic and equilibrium analysis, photoactivation analysis, and membrane isolation.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL056865-04
Application #
6183762
Study Section
Metabolism Study Section (MET)
Project Start
1997-04-01
Project End
2001-03-31
Budget Start
2000-04-01
Budget End
2001-03-31
Support Year
4
Fiscal Year
2000
Total Cost
$283,456
Indirect Cost
Name
Baylor College of Medicine
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
074615394
City
Houston
State
TX
Country
United States
Zip Code
77030
Gillard, Baiba K; Rosales, Corina; Xu, Bingqing et al. (2018) Rethinking reverse cholesterol transport and dysfunctional high-density lipoproteins. J Clin Lipidol 12:849-856
Yelamanchili, Dedipya; Gillard, Baiba K; Gotto Jr, Antonio M et al. (2017) Structural Stability of Streptococcal Serum Opacity Factor. Protein J 36:196-201
Xu, Bingqing; Gillard, Baiba K; Gotto Jr, Antonio M et al. (2017) ABCA1-Derived Nascent High-Density Lipoprotein-Apolipoprotein AI and Lipids Metabolically Segregate. Arterioscler Thromb Vasc Biol 37:2260-2270
Jarrett, Kelsey E; Lee, Ciaran M; Yeh, Yi-Hsien et al. (2017) Somatic genome editing with CRISPR/Cas9 generates and corrects a metabolic disease. Sci Rep 7:44624
Gillard, Baiba K; Bassett, G Randall; Gotto Jr, Antonio M et al. (2017) Scavenger receptor B1 (SR-B1) profoundly excludes high density lipoprotein (HDL) apolipoprotein AII as it nibbles HDL-cholesteryl ester. J Biol Chem 292:8864-8873
Rosales, C; Davidson, W S; Gillard, B K et al. (2016) Speciated High-Density Lipoprotein Biogenesis and Functionality. Curr Atheroscler Rep 18:25
Gillard, Baiba K; Rodriguez, Perla J; Fields, David W et al. (2016) Streptococcal serum opacity factor promotes cholesterol ester metabolism and bile acid secretion in vitro and in vivo. Biochim Biophys Acta 1861:196-204
Rodriguez, Perla J; Gillard, Baiba K; Barosh, Rachel et al. (2016) Neo High-Density Lipoprotein Produced by the Streptococcal Serum Opacity Factor Activity against Human High-Density Lipoproteins Is Hepatically Removed via Dual Mechanisms. Biochemistry 55:5845-5853
Pownall, Henry J; Gotto Jr, Antonio M (2016) New Insights into the High-Density Lipoprotein Dilemma. Trends Endocrinol Metab 27:44-53
Murray, Stephen C; Gillard, Baiba K; Ludtke, Steven J et al. (2016) Direct Measurement of the Structure of Reconstituted High-Density Lipoproteins by Cryo-EM. Biophys J 110:810-6

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