Effects of Clofibric Acid on the Activity and Activity State of the Hepatic Branched-chain 2-oxo Acid Dehydrogenase Complex

Overview

Journal Biochem J

Specialty Biochemistry

Date 1992 Jul 1

PMID 1637295

Citations 5

Authors

Y Zhao

J Jaskiewicz

R A Harris

Affiliations

Soon will be listed here.

Abstract

Feeding clofibric acid to rats caused little or no change in total activity of the liver branched-chain 2-oxo acid dehydrogenase complex (BCODC). No change in mass of liver BCODC was detected by immunoblot analysis in response to dietary clofibric acid. No changes in abundance of mRNAs for the BCODC E1 alpha, E1 beta and E2 subunits were detected by Northern-blot analysis. Likewise, dietary clofibric acid had no effect on the activity state of liver BCODC (percentage of enzyme in the dephosphorylated, active, form) of rats fed on a chow diet. However, dietary clofibric acid greatly increased the activity state of liver BCODC of rats fed on a diet deficient in protein. No stable change in liver BCODC kinase activity was found in response to clofibric acid in either chow-fed or low-protein-fed rats. Clofibric acid had a biphasic effect on flux through BCODC in hepatocytes prepared from low-protein-fed rats. Stimulation of BCODC flux at low concentrations was due to clofibric acid inhibition of BCODC kinase, which in turn allowed activation of BCODC by BCODC phosphatase. Inhibition of BCODC flux at high concentrations was due to direct inhibition of BCODC by clofibric acid. The results suggest that the effects of clofibric acid in vivo on branched-chain amino acid metabolism can be explained by the inhibitory effects of this drug on BCODC kinase.

Citing Articles

Role of branched-chain amino acid metabolism in the pathogenesis of obesity and type 2 diabetes-related metabolic disturbances BCAA metabolism in type 2 diabetes.

Vanweert F, Schrauwen P, Phielix E Nutr Diabetes. 2022; 12(1):35.

PMID: 35931683 PMC: 9356071. DOI: 10.1038/s41387-022-00213-3.

Structure-based design and mechanisms of allosteric inhibitors for mitochondrial branched-chain α-ketoacid dehydrogenase kinase.

Tso S, Qi X, Gui W, Chuang J, Morlock L, Wallace A Proc Natl Acad Sci U S A. 2013; 110(24):9728-33.

PMID: 23716694 PMC: 3683707. DOI: 10.1073/pnas.1303220110.

Down-regulation of rat mitochondrial branched-chain 2-oxoacid dehydrogenase kinase gene expression by glucocorticoids.

Huang Y, Chuang D Biochem J. 1999; 339 ( Pt 3):503-10.

PMID: 10215586 PMC: 1220183.

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.

Paul H, Liu W, Adibi S Biochem J. 1996; 317 ( Pt 2):411-7.

PMID: 8713066 PMC: 1217503. DOI: 10.1042/bj3170411.

Developmental pattern of branched-chain 2-oxo acid dehydrogenase complex in rat liver and heart.

Zhao Y, Denne S, Harris R Biochem J. 1993; 290 ( Pt 2):395-9.

PMID: 8452526 PMC: 1132286. DOI: 10.1042/bj2900395.

References

Ono K, Shioya H, Hakozaki M, Honda K, Mori T, Kochi H . Regulation by induction of branched-chain 2-oxo acid dehydrogenase complex in clofibrate-fed rat liver. Biochem Biophys Res Commun. 1990; 172(1):243-8. DOI: 10.1016/s0006-291x(05)80200-1. View

Hess R, Staubli W, RIESS W . Nature of the hepatomegalic effect produced by ethyl-chlorophenoxy-isobutyrate in the rat. Nature. 1965; 208(5013):856-8. DOI: 10.1038/208856a0. View

Zhang B, Paxton R, Goodwin G, Shimomura Y, Harris R . Preservation of the activity state of hepatic branched-chain 2-oxo acid dehydrogenase during the isolation of mitochondria. Biochem J. 1987; 246(3):625-31. PMC: 1148326. DOI: 10.1042/bj2460625. View

Harris R, Paxton R, Goodwin G, Powell S . Regulation of the branched-chain 2-oxo acid dehydrogenase complex in hepatocytes isolated from rats fed on a low-protein diet. Biochem J. 1986; 234(2):285-94. PMC: 1146564. DOI: 10.1042/bj2340285. View

Goodwin G, Zhang B, Paxton R, Harris R . Determination of activity and activity state of branched-chain alpha-keto acid dehydrogenase in rat tissues. Methods Enzymol. 1988; 166:189-201. DOI: 10.1016/s0076-6879(88)66025-3. View

Honda K, Ono K, Mori T, Kochi H . Control of the activity of branched-chain alpha-keto acid dehydrogenase complex in primary cultured rat hepatocytes. Fukushima J Med Sci. 1989; 35(1):19-27. View

Zhang B, Edenberg H, Crabb D, Harris R . Evidence for both a regulatory mutation and a structural mutation in a family with maple syrup urine disease. J Clin Invest. 1989; 83(4):1425-9. PMC: 303839. DOI: 10.1172/JCI114033. View

Espinal J, Beggs M, Patel H, Randle P . Effects of low-protein diet and starvation on the activity of branched-chain 2-oxo acid dehydrogenase kinase in rat liver and heart. Biochem J. 1986; 237(1):285-8. PMC: 1146979. DOI: 10.1042/bj2370285. View

Harris R, Powell S, Paxton R, Gillim S, Nagae H . Physiological covalent regulation of rat liver branched-chain alpha-ketoacid dehydrogenase. Arch Biochem Biophys. 1985; 243(2):542-55. DOI: 10.1016/0003-9861(85)90531-4. View

10.

Wagenmakers A, Veerkamp J, Schepens J, van Moerkerk H . Effect of clofibrate on branched-chain amino acid metabolism. Biochem Pharmacol. 1985; 34(12):2169-73. DOI: 10.1016/0006-2952(85)90413-7. View

11.

HARPER A, Miller R, Block K . Branched-chain amino acid metabolism. Annu Rev Nutr. 1984; 4:409-54. DOI: 10.1146/annurev.nu.04.070184.002205. View

12.

Wagenmakers A, Schepens J, Veldhuizen J, Veerkamp J . The activity state of the branched-chain 2-oxo acid dehydrogenase complex in rat tissues. Biochem J. 1984; 220(1):273-81. PMC: 1153620. DOI: 10.1042/bj2200273. View

13.

Paxton R, Harris R . Clofibric acid, phenylpyruvate, and dichloroacetate inhibition of branched-chain alpha-ketoacid dehydrogenase kinase in vitro and in perfused rat heart. Arch Biochem Biophys. 1984; 231(1):58-66. DOI: 10.1016/0003-9861(84)90362-x. View

14.

Lazarow P . Assay of peroxisomal beta-oxidation of fatty acids. Methods Enzymol. 1981; 72:315-9. DOI: 10.1016/s0076-6879(81)72021-4. View

15.

Danner D, Sewell E, Elsas L . Clofibric acid and phenylpyruvic acid as biochemical probes for studying soluble bovine liver branched chain ketoacid dehydrogenase. J Biol Chem. 1982; 257(2):659-62. View

16.

Pardridge W, Jones M, Kopple J . Effects of clofibric acid on amino acid metabolism in cultured rat skeletal muscle. Am J Physiol. 1981; 240(2):E203-8. DOI: 10.1152/ajpendo.1981.240.2.E203. View

17.

Paul H, Adibi S . Leucine oxidation and protein turnover in clofibrate-induced muscle protein degradation in rats. J Clin Invest. 1980; 65(6):1285-93. PMC: 371465. DOI: 10.1172/JCI109791. View

18.

Pardridge W . Branched chain amino acid oxidation in cultured rat skeletal muscle cells. Selective inhibition by clofibric acid. J Clin Invest. 1980; 66(1):88-93. PMC: 371509. DOI: 10.1172/JCI109839. View

19.

Paul H, Adibi S . Paradoxical effects of clofibrate on liver and muscle metabolism in rats. Induction of myotonia and alteration of fatty acid and glucose oxidation. J Clin Invest. 1979; 64(2):405-12. PMC: 372133. DOI: 10.1172/JCI109476. View

20.

Parker P, Randle P . Branched chain 2-oxo-acid dehydrogenase complex of rat liver. FEBS Lett. 1978; 90(1):183-6. DOI: 10.1016/0014-5793(78)80325-1. View