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The role of high density lipoprotein compositional and functional heterogeneity in metabolic disease

Gordon, Scott M.

Abstract Details

2012, PhD, University of Cincinnati, Medicine: Pathobiology and Molecular Medicine.
High density lipoproteins (HDL) are complexes of phospholipid, cholesterol and protein that circulate in the blood. Epidemiological studies have demonstrated a strong inverse correlation between plasma levels of HDL associated cholesterol (HDL-C) and the incidence of cardiovascular disease (CVD). Clinically, HDL-C is often measured and used in combination with low density lipoprotein cholesterol (LDL-C) to assess overall cardiovascular health. HDL have been shown to possess a wide variety of functional attributes which likely contribute to this protection including anti-inflammatory and anti-oxidative properties and the ability to remove excess cholesterol from peripheral tissues and deliver it to the liver for excretion, a process known as reverse cholesterol transport. This functional diversity might be explained by the complexity of HDL composition. Recent studies have taken advantage of advances in mass spectrometry technologies to characterize the proteome of total HDL finding that over 50 different proteins can associate with these particles. This adds to a growing body of evidence that supports the global hypothesis of this thesis which is that the total pool of HDL in an individual is composed of numerous subspecies with distinct protein and lipid compositions and therefore will have distinct functional properties. Additionally, we believe that the composition of HDL is dynamic and can change in response to changes in the environment of the blood, as can occur in disease. To test these hypotheses we devised an approach based on three aims. Aim 1: Identify and characterize HDL subspecies based on protein composition. Aim 2: Analyze functional heterogeneity across separated plasma HDL fractions. Aim 3: Examine the effect of type 2 diabetes on HDL subspecies distribution in young adults. To accomplish these goals we have developed novel methods for the separation and fractionation of HDL subspecies from human plasma and their subsequent proteomic and functional analysis. Our findings support the existence of a diverse array of HDL species with distinct functionalities which correlate strongly with specific lipid or protein components of the particle. Additionally, we found that the composition of specific subfractions of HDL are altered in type 2 diabetes and that these fractions can predict vascular health better than LDL-C or HDL-C, suggesting that these may prove to be better biomarkers for cardiovascular risk than the current clinical standard. A detailed understanding of HDL subspeciation will be invaluable in the further development of HDL as a biomarker and therapeutic target not only for cardiovascular disease but a variety of disease states.
Sean Davidson, Ph.D. (Committee Chair)
David Askew, Ph.D. (Committee Member)
Long Lu, Ph.D. (Committee Member)
Francis McCormack, M.D. (Committee Member)
Ranasinghe Silva, Ph.D. (Committee Member)
229 p.

Recommended Citations

Citations

  • Gordon, S. M. (2012). The role of high density lipoprotein compositional and functional heterogeneity in metabolic disease [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1353100684

    APA Style (7th edition)

  • Gordon, Scott. The role of high density lipoprotein compositional and functional heterogeneity in metabolic disease. 2012. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1353100684.

    MLA Style (8th edition)

  • Gordon, Scott. "The role of high density lipoprotein compositional and functional heterogeneity in metabolic disease." Doctoral dissertation, University of Cincinnati, 2012. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1353100684

    Chicago Manual of Style (17th edition)