Mechanism of the Hypolipemic Effect of Clofibrate in Postabsorptive Man

Abstract

A B S T R A C T Splanchnic metabolism of triglycerides and other major substrates was studied in the postabsorptive state in normotriglyceridemic and hypertriglyceridemic human subjects wh}o received A g of clofibrate four times daily for 3 wNk. Transport in blood plasma of triglycerides produced in the splanchnic region was quantified by three methods: (a) measurement of the transsplanchnic gradient of '4C-labeled triglycerides during constant intravenous infusion of [1-"C]palmitate (b) chemical measurement of the transsplanchnic gradient in concenltration of triglycerides of very low density lipoproteins; and (c) determination of clearance of 14C-labeled triglycerides in extrasplanchnic tissues. The first method measures only triglycerides derived from free fatty acids and the last two measure total splanchnic production. In hypertriglyceridemic subjects treated with clofibrate, average rates of total splanchulic production of triglycerides and productioni from free fatty acids were the same as those of conmparable untreated subjects despite a consistent fall in plasma triglyceride levels. The hvpotriglyceridemic effect of the drug was therefore accompanied by improved disposal of triglycerides in extrasplanchnic tissues. In treated normotriglyceridemic subjects, unlike their untreated counterparts, total splanchnic production wvas significantly higlher than prodluction from free fatty acids.

Branched Chain Amino Acid Oxidation in Cultured Rat Skeletal Muscle Cells

“…Therefore, if clofibrate does induce myopathic changes by altering protein turnover in skeletal muscle, one possible mechainism for these events might be a drug-iinduced alteration in leucine metabolism in muscle. Another observation that suggests a possible linkage between clofibrate and branched chain amino acid metabolism in skeletal muscle is the marked hypoalaninemia associated with therapeutic doses of the drug (5). Skeletal muscle is the major site of alanine production (6)(7)(8)(9), and alanine synthesis in muscle cells is coupled to the transamination of the branched chain amino acids (10,11).…”

Effects of intravenously administered fructose and glucose on splanchnic amino acid and carbohydrate metabolism in hypertriglyceridemic men.

“…The groups of subjects are described in Table J*2 Subjects who received f ructose are designated group F and those who received glucose group G. The postabsorptive controls (group C) included four hypertriglyceridemic males previously described (10,11). All subjects were asymptomatic and had no clinical evidence of disordered circulation.…”

“…The infusions of indocyanine green and [9, 10-3H] palmitate were given for 5 and 12 h, respectively. Two subjects of 2 h after starting the isotopic infusion, a right hepatic vein and left brachial artery were catheterized and the blood volume was determined, as previously described (10,11). In two obese subjects, D. B. and G. R., a dorsalis pedis artery was catheterized instead of a brachial artery.…”

“…These were as previously described (10,11,15) for assay of glucose, lactate, glycerol, oxygen, and carbon dioxide. The method of Buhler (16) for counting ['4C] CO2 in blood was modified by substituting an equal volume of hyamine hydroxide for KOH as the trapping agent (17).…”

“…We have studied patients in the fed state after prolonged, hypercaloric, constant, intravenous infusion of 15 h, controls, from a previous study (10,11).…”