Faculty of Pharmaceutical Sciences, Josai University, Saitama, Japan.
Biol Pharm Bull. 2012;35(9):1509-15. doi: 10.1248/bpb.b12-00243.
The effect of fibrates (clofibric acid, bezafibrate and fenofibrate) on the gene expression and activity of 1-acylglycerophosphocholine acyltransferase (LPCAT) was investigated. The administration of 0.1% (w/w) clofibric acid, bezafibrate or fenofibrate in diet for 14 d to rats induced LPCAT activity in hepatic microsomes in the following order: fenofibrate>bezafibrate>clofibric acid. The LPCAT induced by fenofibrate preferred to arachidonoyl-CoA and linoleoyl-CoA to a greater extent than did LPCAT in control microsomes. The treatment with the fibrates resulted in upregulation of the relative expression of mRNAs encoding LPCAT3 and LPCAT4 in the following order: fenofibrate>bezafibrate>clofibric acid. The administration of fibrates did not change the expression of genes encoding either LPCAT1 or LPCAT2. The treatment with fibrates elevated relative levels of both mRNAs encoding Δ6 desaturase (Fads2) and Δ5 desaturase (Fads1) in the order of fenofibrate>bezafibrate>clofibric acid, and the extent of the increase in the level of Δ6 desaturase mRNA was greater than that of Δ5 desaturase. Fatty acid profile in hepatic phosphatidylcholine (PC) was significantly changed by the treatments with fibrates. These results suggest (i) that fibrates induce LPCAT activity in hepatic microsomes by elevating the expression of genes encoding LPCAT3 and LPCAT4, (ii) that the changes in fatty acid profile of hepatic PC are, in part, due to the elevated expression of two isoforms, LPCAT3 and LPCAT4, and (iii) that the ability of fibrates to induce these changes are in the order of fenofibrate>bezafibrate>clofibric acid.
研究了贝特类药物（氯贝酸、苯扎贝特和非诺贝特）对 1-酰基甘油磷酸胆碱酰基转移酶（LPCAT）的基因表达和活性的影响。将 0.1%（w/w）氯贝酸、苯扎贝特或非诺贝特添加到大鼠饮食中 14 天，以下列顺序诱导肝微粒体中的 LPCAT 活性：非诺贝特>苯扎贝特>氯贝酸。与对照微粒体中的 LPCAT 相比，非诺贝特诱导的 LPCAT 更倾向于优先与花生四烯酰辅酶 A 和亚油酸酰辅酶 A 结合。贝特类药物处理导致编码 LPCAT3 和 LPCAT4 的 mRNAs 的相对表达以下列顺序上调：非诺贝特>苯扎贝特>氯贝酸。贝特类药物处理不会改变编码 LPCAT1 或 LPCAT2 的基因的表达。贝特类药物处理以非诺贝特>苯扎贝特>氯贝酸的顺序升高 Δ6 去饱和酶（Fads2）和 Δ5 去饱和酶（Fads1）编码基因的相对水平，并且 Δ6 去饱和酶 mRNA 水平的增加程度大于 Δ5 去饱和酶。贝特类药物处理显著改变了肝磷酯酰胆碱（PC）中的脂肪酸谱。这些结果表明：（i）贝特类药物通过上调编码 LPCAT3 和 LPCAT4 的基因的表达诱导肝微粒体中的 LPCAT 活性；（ii）肝 PC 中脂肪酸谱的变化部分归因于两种同工酶 LPCAT3 和 LPCAT4 的表达上调；（iii）贝特类药物诱导这些变化的能力按非诺贝特>苯扎贝特>氯贝酸的顺序排列。
