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 contradictory results regarding the effect of clofibrate treatment on gene 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 regulates the activity of BCKDH by phosphorylation. The purpose of the present study was to investigate the above issues. Clofibrate treatment for 2 weeks resulted in (a) a 3-fold increase in the flux through BCKDH in mitochondria isolated from rat liver, and (b) a modest but significant increase in the activity of BCKDH. However, clofibrate treatment had no significant effect on the mass of E1 alpha, E1 beta, and E2 subunits of BCKDH or the abundance of mRNAs encoding these subunits. On the other hand, clofibrate treatment significantly reduced the activity, the protein mass and the mRNA levels of BCKDH kinase in the liver. In contrast to the results obtained in liver, clofibrate treatment had no significant effect on any of these parameters of BCKDH kinase in the skeletal muscle. In conclusion, our results show that clofibrate treatment increases the activity of BCKDH in the liver and the mechanism of this effect is the inhibition of gene expression of the BCKDH kinase.
Paul
H S
HS
Department of Medicine, University of Pittsburgh School of Medicine, PA 15261, USA.
Liu
W Q
WQ
Adibi
S A
SA
D042942:3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide); D000818:Animals; D002994:Clofibrate / Q000494:pharmacology*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D000960:Hypolipidemic Agents / Q000494:pharmacology*; D007658:Ketone Oxidoreductases / Q000096:biosynthesis* / Q000235:genetics; D008297:Male; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000201:enzymology; D009097:Multienzyme Complexes / Q000096:biosynthesis* / Q000235:genetics; D018482:Muscle, Skeletal / Q000187:drug effects / Q000201:enzymology; D011494:Protein Kinases / Q000096:biosynthesis* / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley
D000960:Hypolipidemic Agents; D009097:Multienzyme Complexes; D012333:RNA, Messenger; D007658:Ketone Oxidoreductases; D042942:3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide); D011494:Protein Kinases; C035627:(3-methyl-2-oxobutanoate dehydrogenase (lipoamide)) kinase; D002994:Clofibrate