Induction of 1-Acylglycerophosphocholine Acyltransferase Genes by Fibrates in the Liver of Rats

Abstract

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.Key words 1-acylglycerophosphocholine acyltransferase; clofibric acid; bezafibrate; fenofibrate; rat liver 2-(4-Chlorophenoxy)-2-methylpropionic acid (clofibric acid), a hypolipidemic drug, is well known to enhance fatty acid degradation through inducing the proliferation of peroxisomes and fatty acid β-oxidation in the liver.1) In addition to lipid degradation, clofibric acid (or clofibrate) affects lipid biosynthesis of animals through the enzymes such as stearoyl-CoA desaturase (SCD), 2,3) palmitoyl-CoA elongase, 4,5) acyl-CoA synthetase, 5) glycerophosphate acyltransferase, 6) 1-acylglycerophosphate acyltransferase, 5) CoA-dependent transacylase 7) and 1-acylglycerophosphocholine acyltransferase (LPCAT). 8,9) Of these enzymes, LPCAT is of particular interest in relation to the acyl composition of membrane phospholipid. Namely, the primary physiological role of LPCAT is considered to be generation of phosphatidylcholine (PC) having an unsaturated fatty acid at the sn-2 position. 10) A previous study showed that the treatment of rats with clofibric acid caused a marked alteration in acyl composition of PC 5) and, consequently, in the composition of molecular species of PC in the liver.11) The clofibric acid-caused changes in acyl composition of hepatic PC were demonstrated to be the result of the inductions of SCD and LPCAT in the liver. 5,12,13) Although studies focusing on the effect of clofibric acid on the induct...

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