Effects of fatty acids on albumin-mediated cholesterol efflux from endothelial cells and on the growth of hamster pancreatic β-cells

Tuei, Vivian Cherono
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[Honolulu] : [University of Hawaii at Manoa], [December 2010]
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There is compelling evidence that elevated levels of plasma free fatty acids (FFAs) are associated with insulin resistance and pancreatic β-cell dysfunctions. On the other hand, elevated levels of circulating cholesterol are linked with higher incidence of cardiovascular diseases (CVD). CVD and its complications that several type 2 diabetic patients experience are the leading causes of death. Despite these findings on the elevated levels of FFAs in metabolic diseases, the role that the most abundant serum protein and the sole FFA carrier, human serum albumin (HSA), plays in FFA-induced cellular effects is not well studied. HSA binds to many other ligands of both endogenous and exogenous sources, including cholesterol as evidenced through its potency to mediate cholesterol efflux in cell cultures. In this study, we examined the effects of HSA mixed with various FFAs on FFA-induced cell viability changes and insulin secretion from the hamster pancreatic insulinoma cell line, HIT-T15. Our study showed that various FFAs mixed with HSA have differential effects on HIT-TI5 cell viability, depending on the degree of saturation and chain length of FFAs. Furthermore, we showed that palmitate and stearate had adverse effects on cell viability that cylosporin A (csA) and caspase inhibition could not reverse, regardless of the presence of HSA or bovine serum albumin. However, caspase inhibition blocked apoptotic DNA fragmentation, thus indicating that FFA-induced β-cell death is not due to a single mechanism of cell death. Insulin secretion was also reduced after 24-hour exposure of β-cell to HSA/oleate complexes. We further examined the effects of FFAs on HSA-mediated efflux in the endothelial cell-line, EA.hy926. We observed significant reductions in cholesterol efflux (P < 0.05) at HSA/oleate or palmitate molar ratios of 1:5.3; this was not elicited by the presence of arachidonate. These results suggest that palmitate and oleate competes with cholesterol for the same binding site on HSA. Lastly, modified HSA/FFA interactions caused by mutations of key amino acids involved in binding of FFA to HSA resulted in β-cell viability changes as well as on changes in HSA-mediated cholesterol efflux. Our study suggests a possible role of HSA polymorphism in FFA-induced cellular changes.
Ph.D. University of Hawaii at Manoa 2010.
Includes bibliographical references.
Human serum albumin, fatty acid, β-cell, endothelial cell, cholesterol efflux
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Theses for the degree of Doctor of Philosophy (University of Hawaii at Manoa). Molecular Biosciences and Bioengineering.
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