TISSUE-SPECIFIC REGULATION OF MEDIUM-CHAIN ACYL-COA DEHYDROGENASE GENE BY THYROID-HORMONES IN THE DEVELOPING RAT

During development, gene expression of medium-chain acyl-CoA dehydroge nase (MCAD), a nuclear-encoded mitochondrial enzyme that catalyses the first step of medium-chain fatty acid beta-oxidation, is highly regul ated in tissues in accordance with fatty acid utilization, but the fac tors involved in this regulation are largely unknown. To investigate a possible role of thyroid hormones, rat pups were made hypothyroid by the administration of propylthiouracyl to the mother from day 12 of ge station, and their kidneys, heart and liver were removed on postnatal day 16 to determine MCAD mRNA abundance, protein level and enzyme acti vity. Similar experiments were run in 3,3',5-triiodothyronine (T-3)-re placed hypothyroid (1 mu g of T-3/100 g body weight from postnatal day 5 to 15) and euthyroid pups. Hypothyroidism led to an increase in MCA D mRNA abundance in kidney and a decrease in abundance in heart, but h ad no effect in liver. The protein levels and enzyme activity were low ered in hypothyroid heart and kidney, suggesting that hypothyroidism a ffects post-transcriptional steps of gene expression in the kidney. Al l the effects of hypothyroidism were completely reversed in both heart and kidney by T-3 replacement. Injection of a single T-3 dose into 16 -day-old euthyroid rats also led to tissue-specific changes in mRNA ab undance. Nuclear run-on assays performed from hypothyroid and hypothyr oid plus T-3 rats showed that T-3 stimulates MCAD gene transcription i n heart and represses it in the kidney. These results indicate that th e postnatal rise in circulating T-3 is essential to the developmental regulation of the MCAD gene in vivo.