Metabolic acidosis and glucocorticoids act in concert to stimulate branched-chain amino acid (BCAA) oxidation in adrenalectomized rats. In muscles of normal rats, metabolic acidosis increases the maximal activity of the rate-limiting enzyme, branched-chain α-ketoacid dehydrogenase (BCKAD) and a genetic response to catabolic conditions like uremia is implicated by concurrently higher levels of BCKAD subunit mRNA. To determine if acidification or glucocorticoids increase transcription of BCKAD subunit genes, transfection studies were performed with BCKAD promoter-luciferase reporter minigenes in LLC-PK1 cells which do not express gluco-corticoid receptors or LLC-PK1 cells which express a rat glucocorticoid receptor gene (LLC-PK1-GR101). Acidification significantly increased luciferase activity in LLC-PK1 cells and LLC-PK1-GR101 cells transfected with reporter plasmids containing 7.0 kb of E2 subunit or 0.8 kb of E1α subunit promoter region, respectively. Glucocorticoids in the form of dexamethasone induced transcription of these minigenes but only in LLC-PK1-GR101 cells. Using promoter deletion analysis, independent transactivation response elements to acidification or glucocorticoids were localized in the E2 promoter. In summary, catabolic responses to low extracellular pH and glucocorticoids include enhanced expression of genes encoding BCKAD subunits.

Keywords:
Branched-chain amino acids, Gene expression, Branched-chain ketoacid dehydrogenase, Glucocorticoids, Acidification, Acidosis
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2000
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