Date of Award
Doctor of Philosophy
This project was aimed to examine the effects of the progestin d-norgestrel (d-Ng) on lipid and lipoprotein metabolism and elucidate its mechanism of action using the rat as the experimental model.;d-Ng fed to female rats (18 days) in conventional doses, significantly lowered the plasma total and very low density lipoprotein (VLDL)-triglycerides. In contrast, the plasma total and low density lipoprotein (LDL)-cholesterol rose significantly. The triglyceride synthesis was studied using isolated rat hepatocytes. d-Ng (0.1mM), in the presence of 0.1% dimethylsulfoxide concentration of the medium, significantly inhibited the incorporation of both 9,10-('3)H palmitate and U-('14)C glycerol into triglycerides synthesized and triglycerides released by the hepatocytes. The inhibition of triglyceride synthesis by d-Ng was dose-dependent.;Further studies of the effect of d-Ng on the rate limiting enzymes of triglyceride synthesis showed a significant reduction in the specific activity of hepatic glycerol phosphate acyltransferase (GPAT) and phosphatidic acid aqueous dependent phosphatidic acid phosphatase (PAPase) specifically in the microsomes. However, the specific activity of mitochondrial GPAT and phosphatidic acid membrane bound dependent PAPase in microsomes as well as cytosol remained unchanged. These findings suggest that d-Ng acts by inhibiting specifically the hepatic lipogenic enzymes in the microsomes. This subsequently reduces the triglyceride synthesis and secretion by the liver resulting in lower plasma and VLDL triglycerides levels in d-Ng-treated rats.;Studies of VLDL and LDL turnover were carried out by examining the kinetics of labelled apolipoprotein-B of VLDL and LDL (isolated from human and rat plasma) injected into d-Ng-treated and control rats. Analysis of specific activity time curves showed a higher fractional catabolic rate (FCR) of VLDL-apolipoprotein-B compared to controls. This explained the reduction in the pool size of VLDL-apolipoprotein-B because the production rate was unaffected. In contrast to VLDL-apolipoprotein-B, the FCR of LDL-apolipoprotein-B was markedly lower in d-Ng treated rats. This caused the larger pool size of LDL-apolipoprotein-B, since production rate was similar in the two groups. The primary effect of d-Ng on both the lipoproteins was on their efficiency of removal from the plasma. These divergent effects of d-Ng explain both its triglyceride-lowering and cholesterol-elevating effects in rats.
Khokha, Rama, "Effects Of D-norgestrel On Lipid Metabolism In The Rat" (1985). Digitized Theses. 1415.