Mechanism of the hypolipemic effect of clofibrate in glucose-fed men

Abstract

Studies were undertaken in man to ascertain the mechanism of the triglyceride-lowering effect of clofibrate in the glucose-fed state. Test subjects received 0.5 g clofibrate four times daily for 3 wk prior to the study of splanchnic metabolism. Splanchnic metabolism of triglycerides and other substrates was studied during prolonged intravenous administration of labeled palmitic acid and glucose (30 g/hr) to hypertriglyceridemic men maintained on a high carbohydrate diet for 2 wk. The secretion of plasma triglycerides from the splanchnic region was quantified from splanchnic flow and radiochemical measurements of the transsplanchnic gradients of labeled free fatty acids and triglycerides. Total transport of plasma triglycerides was also estimated in the test subjects from teh turnover of plasma very low density lipoproteins (VLDL)- 3H-triglycerides following pulse labeling with 2- 3H-glycerol. Clofibrate prevented the rise in fasting plasma triglyceride concentration which was expected to occur during the administration of the hypercaloric high carbohydrate diet. Mean plasma triglyceride fatty acids were 35% lower than control values (6.5 ± 1.3 vs. 10.0 ± 2.2 m M) and splanchnic secretion of triglycerides 68% lower in clofibrate-treated subjects than controls (32 ± 6 vs. 100 ± 40 μmol/min.m 2, p<0.05). Although systemic transport and splanchnic uptake and conversion of free fatty acids to plasma triglycerides were unaltered by clofibrate, the mean fraction of triglyceride fatty acids of plasma VLDL derived from precursors other than free fatty acids was significantly lower in subjects receiving clofibrate than controls (73 ± 6 vs. 91 ± 1%). Net splanchnic uptake of oxygen and glycerol and the release of lactate were lower in test subjects than controls, whereas splanchnic uptake of serine, histidine, and aspartate was increased. The triglyceride-lowering effect of clofibrate in the glucose-fed state was attributable to inhibition of hepatic secretion of triglycerides.