Paul H S, Liu W Q, Adibi S A
Department of Medicine, University of Pittsburgh School of Medicine, PA 15261, USA.
Biochem J. 1996 Jul 15;317 ( Pt 2)(Pt 2):411-7. doi: 10.1042/bj3170411.
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.
我们先前发现，用氯贝丁酯治疗的大鼠中支链氨基酸的氧化作用增强[保罗和阿迪比（1980年）《临床研究杂志》65卷，第1285 - 1293页]。随后的两项研究报告了关于氯贝丁酯治疗对大鼠肝脏中支链酮酸脱氢酶（BCKDH）基因表达影响的相互矛盾的结果。此外，此前尚无关于氯贝丁酯治疗对BCKDH激酶基因表达影响的研究，BCKDH激酶通过磷酸化作用调节BCKDH的活性。本研究的目的是探讨上述问题。氯贝丁酯治疗2周导致：（a）从大鼠肝脏分离的线粒体中通过BCKDH的通量增加了3倍，以及（b）BCKDH的活性有适度但显著的增加。然而，氯贝丁酯治疗对BCKDH的E1α、E1β和E2亚基的质量或编码这些亚基的mRNA丰度没有显著影响。另一方面，氯贝丁酯治疗显著降低了肝脏中BCKDH激酶的活性、蛋白质质量和mRNA水平。与在肝脏中获得的结果相反，氯贝丁酯治疗对骨骼肌中BCKDH激酶的任何这些参数均无显著影响。总之，我们的结果表明，氯贝丁酯治疗可增加肝脏中BCKDH的活性，且这种作用的机制是抑制BCKDH激酶的基因表达。
