ACTION OF THE NEW HYPOLIPIDEMIC AGENT LIFIBROL (K12.148) ON LIPID HOMEOSTASIS IN NORMAL RATS - PLASMA-LIPIDS, HEPATIC STEROLOGENESIS, AND THE FATE OF INJECTED [C-14] ACETATE

Lifibrol, a new hypocholesterolemic agent with activity in humans, was examined in normal rats for its short-term and long-term effects on lipid homeostasis. Cholesterol (Chol) synthesis inhibition by lifibrol was demonstrated in vitro in liver minces from normal rats by following [1-C-14]acetate ([C-14]Ac) and DL-[2-C-14]mevalonate ([C-14]-MVA) incorporation into [C-14]Chol. When administered at 50 mg/kg/d, lifibrol reduced plasma total Chol and triglycerides (TG) (P < 0.001) within 24 h. The Chol reduction was largely a result of reduction of low density and very low density lipoprotein cholesterol (LDL + VLDL-chol) and a smaller decrease in high density lipoprotein cholesterol (HDL-chol). After 10 d, however, a rebound effect emerged, and after 41 d, plasma Chol, LDL + VLDL-chol, and HDL-chol were restored. In contrast, plasma TG remained at reduced levels (P < 0.01). The rebound is attributed to counter-regulation of hepatic sterologenesis that was assessed both ex vivo and in vivo. The ex vivo incorporation of [C-14]MVA and [C-14]octanoate into [C-14]Chol and total digitonin-precipitable [C-14]sterols ([C-14]DPS) in liver minces was increased 2-and 6-fold, respectively, in rats treated 6 d at 50 mg/kg. Similarly, in vivo incorporation of intraperitoneally injected [C-14]Ac into hepatic [C-14]DPS (2 h post-injection) was increased 2- to 5-fold at 50 mg/kg, and evidence for increased sterologenesis in nonhepatic tissue was also obtained. The increased hepatic sterologenesis, evident within 48 h, persisted out to 41 d of treatment by which time increases (P < 0.002) in hepatic Chol and carcass total sterols were observed. Additionally, incorporation of injected [C-14]Ac into hepatic [C-14]TG was inhibited 60% by lifibrol (P < 0.001), and the appearance of [C-14]TG in plasma was reduced. Circulating free [C-14]fatty acids ([C-14]FFA) were also reduced, but hepatic [C-14]FFA synthesis was unaffected, thus suggesting either a lesser release of newly formed FFA from liver or an enhanced removal from plasma.