ALTERATION IN GENE-EXPRESSION OF BRANCHED-CHAIN KETO ACID DEHYDROGENASE KINASE BUT NOT IN GENE-EXPRESSION OF ITS SUBSTRATE IN THE LIVER OF CLOFIBRATE-TREATED RATS

We previously showed that the oxidation of branched-chain amino acids is increased in rats treated with clofibrate [Paul and Adibi (1980) J. Clin. Invest. 65, 1285-1293]. Two subsequent studies have reported co ntradictory results regarding the effect of clofibrate treatment on ge ne expression of branched-chain keto acid dehydrogenase (BCKDH) in rat liver. Furthermore, there has been no previous study of the effect of clofibrate treatment on gene expression of BCKDH kinase, which regula tes the activity of BCKDH by phosphorylation. The purpose of the prese nt study was to investigate the above issues. Clofibrate treatment for 2 weeks resulted in (a) a 3-fold increase in the flux through BCKDH i n mitochondria isolated from rat liver, and (b) a modest but significa nt increase in the activity of BCKDH. However, clofibrate treatment ha d no significant effect on the mass of E(1) alpha, E(1) beta, and E(2) subunits of BCKDH or the abundance of mRNAs encoding these subunits. On the other hand, clofibrate treatment significantly reduced the acti vity, the protein mass and the mRNA levels of BCKDH kinase in the live r. In contrast to the results obtained in liver, clofibrate treatment had no significant effect on any of these parameters of BCKDH kinase i n the skeletal muscle. In conclusion, our results show that clofibrate treatment increases the activity of BCKDH in the liver and the mechan ism of this effect is the inhibition of gene expression of the BCKDH k inase.