| الوصف: |
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‐ 14 C]acetate ([ 14 C]Ac) and DL‐[2‐ 14 C]mevalonate ([ 14 C]‐MVA) incorporation into [ 14 C]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 [ 14 C]MVA and [ 14 C]octanoate into [ 14 C]Chol and total digitonin‐precipitable [ 14 C]sterols ([ 14 C]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 [ 14 C]Ac into hepatic [ 14 C]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 [ 14 C]Ac into hepatic [ 14 C]TG was inhibited 60% by lifibrol ( P <0.001), and the appearance of [ 14 C]TG in plasma was reduced. Circulating free [ 14 C]fatty acids ([ 14 C]FFA) were also reduced, but hepatic [ 14 C]FFA synthesis was unaffected, thus suggesting either a lesser release of newly formed FFA from liver or an ... |
