Brass E P, Ruff L J
Department of Medicine, Case Western Reserve University, Cleveland, Ohio.
J Pharmacol Exp Ther. 1991 Jun;257(3):1034-8.
Prostaglandins (PG) modulate hepatocyte glucose and lipid metabolism. Hepatocytes rapidly metabolize PG via beta-oxidation, terminating PG action. Clofibrate induces hepatic peroxisomal beta-oxidative activity, for which PG are substrates. To determine the effect of clofibrate-treatment on liver PG metabolism and action, hepatocytes were isolated from rats maintained on a control or clofibrate-supplemented (0.5%) diet for 7 to 9 days. Rates of PG catabolism were determined by high performance liquid chromatography resolution of [3H]PG from [3H]metabolites. Clofibrate treatment enhanced the rates of PGE2, PGF2, and PGD2 degradation by 85%, 278% and 137%, respectively. Rates of PG degradation were correlated with hepatocyte carnitine acetyltransferase activity, a marker of peroxisomal proliferation. Further evidence of enhanced hepatocyte peroxisomal beta-oxidation of PG after clofibrate-treatment was obtained by confirming loss of the 1-position carbon from [1-14C]PGE2 during PGE2 metabolism and failure of the carnitine acyltransferase inhibitor acetyl-DL-aminocarnitine to inhibit PGE2 metabolism. Associated with the faster degradation of PGE2 by hepatocytes from clofibrate-treated rats was loss of inhibition of hepatocyte glucagon-stimulated glycogenolysis by exogenous PGE2. Thus, clofibrate's induction of peroxisomal beta-oxidation is associated with accelerated catabolism of PG and decreased PG action. Alterations in PG breakdown provide a mechanism for modulating hepatic PG effects.
前列腺素（PG）可调节肝细胞的葡萄糖和脂质代谢。肝细胞通过β-氧化迅速代谢PG，从而终止PG的作用。氯贝丁酯可诱导肝脏过氧化物酶体β-氧化活性，而PG是该氧化过程的底物。为了确定氯贝丁酯治疗对肝脏PG代谢及作用的影响，从分别以对照饮食或添加氯贝丁酯（0.5%）饮食喂养7至9天的大鼠中分离肝细胞。通过高效液相色谱法从[³H]代谢产物中分离[³H]PG来测定PG分解代谢率。氯贝丁酯治疗分别使PGE₂、PGF₂和PGD₂的降解率提高了85%、278%和137%。PG降解率与肝细胞肉碱乙酰转移酶活性相关，肉碱乙酰转移酶是过氧化物酶体增殖的标志物。通过确认PGE₂代谢过程中[¹-¹⁴C]PGE₂的1位碳原子丢失以及肉碱酰基转移酶抑制剂乙酰-DL-氨基肉碱未能抑制PGE₂代谢，获得了氯贝丁酯治疗后肝细胞PG过氧化物酶体β-氧化增强的进一步证据。与氯贝丁酯治疗大鼠的肝细胞对PGE₂降解加快相关的是，外源性PGE₂对肝细胞胰高血糖素刺激的糖原分解的抑制作用丧失。因此，氯贝丁酯诱导的过氧化物酶体β-氧化与PG分解代谢加速和PG作用减弱有关。PG分解的改变为调节肝脏PG效应提供了一种机制。
