Transport kinetics of plasma free fatty acid, very low density lipoprotein triglycerides and apoprotein in patients with endogenous hypertriglyceridaemia Effect of 2,2-dimethyl, 5(2,5-xylyloxy) valeric acid therapy

Abstract

The effects of C1-719 on plasma lipid and lipoprotein concentrations have been examined in four patients with endogenous hypertriglyceridaemia maintained on an isocaloric diet for a period of 6 months. During therapy (400 mg/day) the mean plasma triglyceride and cholesterol concentrations were reduced by 35% and 15% respectively, while the administration of 800 mg/day reduced these by 49% and 31%. This hypolipidaemic effect was due to a reduction in the circulating level of very low density lipoproteins (VLDL) without a change in their composition. Before treatment the plasma VLDL triglyceride turnover, and FFA flux, were higher than that of normal subjects maintained on a similar diet. The plasma VLDL B-apoprotein turnover was similarly higher than in the controls. Administration of C1-719 decreased the plasma VLDL triglyceride turnover, FFA flux and VLDL B-apoprotein turnover. The drug reduced the insulin response following a glucose load with some decrease in glucose levels. The results suggest tha the increase in plasma triglyceride concentration in patients with endogenous hypertriglyceridaemia is due to increased production of plasma VLDL triglyceride and its apoprotein associated with an enhanced supply of FFA for hepatic triglyceride synthesis. Cl-719 exerts a hypolipidaemic effect through a reduction of VLDL production, consequent upon inhibition of lipolysis as well as decreased synthesis of the apoprotein carrier. These effects could in part be explained by an improvement in peripheral tissue responsiveness to insulin and a decreased exposure of the liver to high levels of insulin. However, a direct effect of the drug on adipose tissue and liver metabolism has to be considered.