The principal aim of this program project is to delineate the processes that give rise to the multiple subclasses of human plasma lipoproteins, thereby to better understand the influence of genetic and environmental factors on plasma lipid transport and the development of atherosclerosis. A wide range of scientific disciplines and experimental approaches will be used, including human and molecular genetics, metabolism, cell biology, biochemistry, biophysics, mathematics and statistics. The program is organized into five highly interactive Projects and three Core units which provide support services used by each of the projects. Project 1 is aimed at determining the influence of genetic and metabolic factors on the distribution and properties of human low density lipoprotein (LDL) subclasses and to refine genetic models for the heritability of lipoprotein subclass phenotypes. The structural, metabolic, and genetic implications of recently demonstrated differences in glycosylation of apolipoprotein (apo) B across the LDL particle spectrum will be investigated in detail. In Project 2, model lipoprotein systems will be used to define the physical-chemical and metabolic bases for speciation, remodeling and function of nascent and plasma apo-specific high density lipoprotein (HDL) subpopulations. A major focus will be on the influence of triglyceride- rich lipoprotein metabolism on the formation and properties of HDL subclasses, and on their function in intravascular and extravascular cholesterol transport. Project 3 further examines the critical link between triglyceride-rich lipoproteins and the formation and metabolism of LDL and HDL subclasses by investigating the role of lipolysis products in mediating physical interactions and transfers among lipoprotein particles. Specific processes to be studied include the direct removal of surface lipids from remnants by HDL proteins, the binding of LDL to remnants, and the roles of these processes in forming HDL and LDL subclasses and in influencing remnant metabolism. In Project 4, the in vivo origins of HDL subclasses, their structural and regulatory determinants, and their influence on lipoprotein metabolism and atherosclerosis will be investigated in transgenic mice carrying the human genes for apoAI and apoAII, the major HDL protein constituents. Cell culture systems will be employed in Project 5 to delineate the cellular origins of apo-specific HDL subpopulations and to study the influence of apoAI and apoAII gene expression on this process. Hepatic cell cultures will also be used to further investigate the relationship of varying apoB glycosylation with LDL subclass formation and metabolism. The Lipoprotein Analysis Core will provide standardized measurements of lipids, lipoproteins, and apolipoproteins for all Projects, and will also serve as a resource for specialized analytic and preparative procedures. The Computation and Statistics Core will support data acquisition, analysis and storage, while the Administrative Core will oversee and coordinate all scientific and support activities, including the clinic. In summary, this Program Project provides an integrated, multidisciplinary approach to the understanding of mechanisms influencing the properties, functions, interrelationships, and clinical significance of lipoprotein subclasses.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL018574-18
Application #
3097647
Study Section
Heart, Lung, and Blood Research Review Committee B (HLBB)
Project Start
1976-04-01
Project End
1997-03-31
Budget Start
1993-04-01
Budget End
1994-03-31
Support Year
18
Fiscal Year
1993
Total Cost
Indirect Cost
Name
Lawrence Berkeley National Laboratory
Department
Type
Organized Research Units
DUNS #
078576738
City
Berkeley
State
CA
Country
United States
Zip Code
94720
Ma, Ke; Forte, Trudy; Otvos, James D et al. (2005) Differential additive effects of endothelial lipase and scavenger receptor-class B type I on high-density lipoprotein metabolism in knockout mouse models. Arterioscler Thromb Vasc Biol 25:149-54
Kwiterovich Jr, Peter O; Cockrill, Steven L; Virgil, Donna G et al. (2005) A large high-density lipoprotein enriched in apolipoprotein C-I: a novel biochemical marker in infants of lower birth weight and younger gestational age. JAMA 293:1891-9
Dubrac, Sandrine; Lear, Steven R; Ananthanarayanan, Meena et al. (2005) Role of CYP27A in cholesterol and bile acid metabolism. J Lipid Res 46:76-85
Williams, Paul T; Blanche, Patricia J; Rawlings, Robin et al. (2005) Concordant lipoprotein and weight responses to dietary fat change in identical twins with divergent exercise levels 1. Am J Clin Nutr 82:181-7
Krauss, Ronald M (2005) Dietary and genetic probes of atherogenic dyslipidemia. Arterioscler Thromb Vasc Biol 25:2265-72
Badzioch, Michael D; Igo Jr, Robert P; Gagnon, France et al. (2004) Low-density lipoprotein particle size loci in familial combined hyperlipidemia: evidence for multiple loci from a genome scan. Arterioscler Thromb Vasc Biol 24:1942-50
Berneis, Kaspar; Shames, David M; Blanche, Patricia J et al. (2004) Plasma clearance of human low-density lipoprotein in human apolipoprotein B transgenic mice is related to particle diameter. Metabolism 53:483-7
Rizzo, Manfredi; Taylor, John M; Barbagallo, Carlo M et al. (2004) Effects on lipoprotein subclasses of combined expression of human hepatic lipase and human apoB in transgenic rabbits. Arterioscler Thromb Vasc Biol 24:141-6
Georgieva, A M; van Greevenbroek, M M J; Krauss, R M et al. (2004) Subclasses of low-density lipoprotein and very low-density lipoprotein in familial combined hyperlipidemia: relationship to multiple lipoprotein phenotype. Arterioscler Thromb Vasc Biol 24:744-9
Mar, Rebecca; Pajukanta, Paivi; Allayee, Hooman et al. (2004) Association of the APOLIPOPROTEIN A1/C3/A4/A5 gene cluster with triglyceride levels and LDL particle size in familial combined hyperlipidemia. Circ Res 94:993-9

Showing the most recent 10 out of 233 publications