published_or_final_version / abstract / Surgery / Master / Master of Philosophy

published_or_final_version / Medicine / Doctoral / Doctor of Philosophy

published_or_final_version / Community Medicine / Master / Master of Public Health

abstract / Pathology / Doctoral / Doctor of Philosophy

The metabolic fate of cholesterol delivered to rat hepatocytes by rat plasma lipoproteins was determined. Binding and degradation of rat low and high density lipoproteins (LDL and HDL) in rat hepatocytes were studied. ¹²⁵I-labelled LDL and HDL were incubated with cells in the presence of varying concentrations of unlabelled lipoproteins for two hours at 37°C. The amount of ¹²⁵I-LDL and ¹²⁵I-HDL binding and degradation decreased by increasing concentrations of respective unlabelled lipoproteins. The presence of 50-fold excess of unlabelled LDL or HDL resulted in a reduction of ¹²⁵I-LDL and ¹²⁵I-HDL bindings by 66-82%, and degradations by 63-88%, respectively. Equilibrium dissociation constants (K [subscript d]) determined by Scatchard analysis for HDL (.15 x 10⁻⁸M) and LDL (1.04 x 10⁻⁸M) revealed that HDL have approximately 7-fold higher binding affinity for receptors on cell surface than LDL. Specific use of LDL and HDL-cholesterol for bile acid synthesis by rat hepatocytes was investigated. When LDL and HDL labelled with ³H-LDL cholesterol was transformed to bile acids mostly as lithocholic, chenodeoxy and deoxycholic acids. A technique developed for isolation of hepatocytes from rat liver was described. Once isolated by the technique most cells retained their microscopic structural integrity, and excluded trypan blue. The viability was 93%, which decreased to 86% after four hours of incubation. The presented data demonstrated that both HDL and LDL bind to specific receptors on hepatocytes and undergo proteolytic degradation in rats. The study also showed that the binding affinity of HDL to hepatic receptors was much greater than that of LDL but in total binding LDL uptake was four times greater than HDL, suggesting the presence of two specific binding sites for HDL and LDL. The first direct evidence for the preferential utilization of HDL-cholesterol for biosynthesis of bile acids in vivo is presented. This finding is compatible with the current concept of HDL as the protective lipoprotein against developing coronary heart disease. / Graduation date: 1985

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