Combined interaction of phospholipase C and apolipoprotein A-I with small unilamellar vesicles in the context of gallstone disease /

by Gudheti, Manasa V.; Wrenn, Steven Parker; College of, Drexel University.

Combined interaction of phospholipase C and apolipoprotein A-I with small unilamellar vesicles in the context of gallstone disease Manasa V. Gudheti Advisor: Steven P. Wrenn, Ph.D. Gallstone disease is the most common gastrointestinal disease that afflicts 10-15% of the US population with an annual cost of over $10.5 billion. Though the aetiolgy of the disease is well understood, more research is warranted regarding the pathogenesis. Knowledge about the gallstone pathway will aid in the measures for prophylactic management. Gallstones form due to the precipitation of cholesterol from cholesterolsupersaturated bile. Small unilamellar vesicles (SUVs) are the predominant transporters of cholesterol in bile. Precipitation of cholesterol monohydrate crystals from aggregated and/or fused SUVs in cholesterol-supersaturated bile followed by crystal accretion and growth leads to gallstone formation. The rate at which cholesterol nucleates from the vesicles, which is influenced by a host of biliary factors, plays a pivotal role in determining the lithogenicity of bile. The kinetic factors are divided into pro-nucleating and anti-nucleating factors that enhance and inhibit nucleation respectively. The balance between the two factors is largely responsible for the incidence of gallstones. This research focuses on understanding the concerted influence of phospholipase C (PLC), a pro-nucleating enzyme, and apolipoprotein (apo A-I), an anti-nucleating protein, on small unilamellar vesicles. We find that apo A-I exerts its anti-nucleating protection via two mechanisms, anti-aggregation and complex formation. The mode of protection is dependent on the vesicle composition, and PLC and apo A-I concentrations. xv It has been previously speculated that apo A-I/lipid complexes exist in bile and this research effort provides proof and confirms prior allusions. The similarities in physical chemistry between gallstone disease and atherosclerosis enable this research to be applied in the study of coronary heart disease. 1