The effects of human serum albumin mutations on physiologically important fatty acid transport

Thesis (M.S.)--University of Hawaii at Manoa, 2007.Includes bibliographical references (leaves 46-54).x, 54 leaves, bound ill. 29 cmHuman Serum Albumin (HSA) is the most abundant plasma protein that transports a variety of drugs and endogenous compounds. HSA is the primary transporter for delivering free fatty acid (FFA) to tissues and possesses at least eleven binding sites for this ligand. Although most FFAs are bound to albumin, a small fraction dissociates from the protein and exists in monomeric form within the aqueous phase, referred to as the unbound free fatty acid (uFFA). The interaction of FFA and HSA serves to buffer the level of FFA in serum and therefore regulates the rate at which FFA is transported to appropriate target cells. Since a close relationship of elevated FFA levels to the incidence of Type 2 Diabetes (T2D) have been shown, the HSA/FFA interactions might therefore indicate HSA's role in the pathogenesis of diabetes by modulating fatty acid availability. Most hydrophobic ligands that bind to HSA such as FFAs bind to one or two distinct high affinity binding pockets or sites in subdomains IIA and IIIA of HSA. In this study, site-directed mutagenesis and a novel protein expression system called Pichia pastoris system were used to synthesize recombinant HSA proteins with specific mutations on key amino acid residues that are involved in FFA binding on these domains. Binding affinities of recombinant HSA and mutant proteins for long chain FAs (palmitate and oleate) were determined by using a fluorescent probe composed of Acrylodan-Derivatized Intestinal Fatty Acid Binding protein (ADIFAB) FFA quantification method. The modified FFA binding affinity induced by mutations in FA binding sites of HSA may provide the rationale background for further studies associated with cellular HSAIFF A interactions and HSA polymorphism

Conceptualising metabolic disorder in Southern Africa: Biology, history and global health

This paper traces the history of the concept of metabolic disorder in global health and its application to the collection of health metrics relating to the ‘epidemic’ of non-communicable diseases in Southern Africa, with a focus on Malawi. Although the contemporary science of metabolism points to complexity and contingency, the application of a simplified version of ‘metabolic disorder’ or ‘metabolic syndrome’ as the supposed central driver of non-communicable disease in low- and middle-income countries runs the risk of obscuring the ways in which local circumstances and histories interact with global forces to produce epidemiological change. The paper discusses health data collection and its interpretation in Malawi to demonstrate how the use of this concept has led to a narrowing of the category of non-communicable disease and a neglect of the role of infectious disease in producing chronic conditions. Finally, the paper points to alternative approaches which might yield a better understanding of pressing health problems