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Articles

Protein Expressions of Branched-Chain Keto Acid Dehydrogenase Subunits Are Selectively and Posttranscriptionally Altered in Liver and Skeletal Muscle of Starved Rats¹

Clinical Nutrition Research Unit, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213

²To whom correspondence should be addressed at UPMC Health System, 200 Lothrop Street, MUH E-321, Pittsburgh, PA 15213. E-mail: adibi{at}msx.dept-med.pitt.edu

Although it has been well established that starvation increases the oxidation of branched-chain keto acids (BCKA) in humans and experimental animals such as rats, the mechanism has not been adequately investigated. For example, the effects of starvation on protein and mRNA expressions of BCKA dehydrogenase, which is the key enzyme regulating this oxidation, have not yet been studied. To initiate such studies, we first determined the activity of BCKA dehydrogenase in the liver and skeletal muscle of fed and starved rats. The levels of activity of BCKA dehydrogenase were significantly greater in tissues of starved rats than in those of fed rats. We then investigated the possible mechanisms of these increases in enzyme activity. The activity state of the enzyme was greater by 3-fold in the muscle of starved compared with fed rats, but there was no significant difference between the activity states in the liver. There were no significant differences between protein expressions of BCKA dehydrogenase subunits (E₁, E₁ß and E₂) in tissues of fed and starved rats; the exceptions were a greater expression of E₁ in the liver and a lower expression of E₁ß in the skeletal muscle of starved rats. These differences in protein expressions were not accompanied with any difference in the mRNA expressions of genes encoding E₁ and E₁ß. The rate of inactivation of BCKA dehydrogenase, mediated by its associated kinase, was significantly slower in the skeletal muscle of starved rats but was the same in the liver. However, there was no significant difference between the protein or the mRNA expressions of the gene encoding BCKA dehydrogenase kinase in tissues of fed and starved rats. These results show that starvation increases the activity of BCKA dehydrogenase in the liver and skeletal muscle, and the mechanisms of increases in activity are posttranscriptional and involve cellular rather than the molecular mechanisms.

KEY WORDS: • branched-chain keto acid oxidation • gene expression • multienzyme complex • BCKA dehydrogenase kinase • metabolic regulation • rats