Capuzzi D M, Intenzo C M, Lackman R D, Whereat A F, Scott D M
Biochem Pharmacol. 1983 Jul 15;32(14):2195-203. doi: 10.1016/0006-2952(83)90226-5.
The acute effects of sodium clofibrate (NaCPIB) on the metabolism of [1-14C]palmitate, [1-14C]octanoate, [1-14C]butyrate, and [2-3H]glycerol by freshly isolated hepatocytes were tested to explore its mechanism of action. Labeled long-, medium-, and short-chain fatty acids were incorporated into all the major lipid classes and were oxidized to 14CO2 by the liver cells. The partitioning of labeled fatty acids from lipogenic towards oxidative pathways was inversely related to fatty acid chain length. [1-14C]Palmitate was incorporated mainly into cellular triglycerides and phospholipids; [1-14C]octanoate, mainly into triglycerides and free cholesterol; and [1-14C]butyrate, mainly into free cholesterol and phospholipids of the cells. NaCPIB (1-3 mM) rapidly stimulated the esterification of labeled palmitate or glycerol to triglycerides, but drug levels greater than 5 mM were inhibitory to esterification. NaCPIB (1 mM) increased the oxidation of [1-14C]palmitate to 14CO2 by either rat or monkey hepatocytes and enhanced the release of labeled lipids from [2-3H]glycerol-prelabeled cells into the extracellular medium. Accelerated [1-14C]octanoate incorporation into glycerolipids and sterols and increased [1-14C]octanoate conversion to 14CO2 were observed in rat liver cells incubated with 1 mM NaCPIB. In contrast, the same drug level stimulated the oxidation of [1-14C]butyrate to 14CO2 but greatly diminished its incorporation into hepatocellular sterols or glycerolipids. These results indicate that (a) NaCPIB acutely alters hepatic ultilization of fatty acids by actions at diverse loci; (b) these metabolic alterations vary with fatty acid chain length; and (c) these effects are probably due to rapid changes in biochemical regulatory mechanism and/or in substrate channelling within the cells. These data further suggest that the early hypolipidemic effect of the drug in rats and primates may be related to an enhanced hepatic oxidation of long-chain fatty acids, but cannot be attributed simply to a reduction in their esterification to complex lipids.
测试了氯贝丁酯钠（NaCPIB）对新鲜分离的肝细胞代谢[1-14C]棕榈酸、[1-14C]辛酸、[1-14C]丁酸和[2-3H]甘油的急性影响，以探究其作用机制。标记的长链、中链和短链脂肪酸被纳入所有主要脂质类别，并被肝细胞氧化为14CO2。标记脂肪酸从生脂途径向氧化途径的分配与脂肪酸链长度呈负相关。[1-14C]棕榈酸主要掺入细胞甘油三酯和磷脂中；[1-14C]辛酸主要掺入甘油三酯和游离胆固醇中；[1-14C]丁酸主要掺入细胞的游离胆固醇和磷脂中。NaCPIB（1-3 mM）迅速刺激标记的棕榈酸或甘油酯化生成甘油三酯，但药物浓度大于5 mM时对酯化有抑制作用。NaCPIB（1 mM）可增加大鼠或猴肝细胞将[1-14C]棕榈酸氧化为14CO2的能力，并增强[2-3H]甘油预标记细胞中标记脂质向细胞外培养基的释放。在用1 mM NaCPIB孵育的大鼠肝细胞中，观察到[1-14C]辛酸加速掺入甘油脂和固醇中，且[1-14C]辛酸转化为14CO2增加。相反，相同药物浓度刺激[1-14C]丁酸氧化为14CO2，但大大减少其掺入肝细胞固醇或甘油脂中的量。这些结果表明：（a）NaCPIB通过在不同位点起作用急性改变肝脏对脂肪酸的利用；（b）这些代谢改变随脂肪酸链长度而变化；（c）这些作用可能是由于细胞内生化调节机制和/或底物通道的快速变化。这些数据进一步表明，该药物在大鼠和灵长类动物中的早期降血脂作用可能与肝脏对长链脂肪酸氧化增强有关，但不能简单地归因于其酯化生成复合脂质的减少。
