Uteroplacental Insufficiency Alters Liver and Skeletal Muscle Branched-Chain Amino Acid Metabolism in Intrauterine Growth-Restricted Fetal Rats

Abstract

Uteroplacental insufficiency causes intrauterine growth restriction (IUGR) and decreases plasma levels of the branchedchain amino acids in both humans and rats. Increased fetal oxidation of these amino acids may contribute to their decline in the IUGR fetus. The rate-limiting step of branched-chain amino acid oxidation is performed by the mitochondrial enzyme branched-chain ␣-keto acid dehydrogenase (BCKAD), which is regulated by a deactivating kinase. We therefore hypothesized that uteroplacental insufficiency increases BCKAD activity through altered mRNA and protein levels of BCKAD and/or the BCKAD kinase. In IUGR fetal liver, BCKAD activity was increased 3-fold, though no difference in hepatic BCKAD protein or mRNA levels were noted. Hepatic BCKAD kinase mRNA and protein levels were significantly decreased in association with the increase in BCKAD activity. In IUGR fetal skeletal muscle, BCKAD mRNA levels were significantly increased. IUGR skeletal muscle BCKAD protein levels as well as BCKAD kinase mRNA and protein levels were unchanged. We also quantified mRNA levels of two amino acid transporters: LAT1 (system L) and rBAT (cysteine and dibasic amino acids). Both hepatic and muscle LAT1 mRNA levels were significantly increased in the IUGR fetus. We conclude that uteroplacental insufficiency significantly increases hepatic BCKAD activity in association with significantly decreased mRNA and protein levels of the deactivating kinase. We speculate that these changes contribute to the decreased serum levels of branched-chain amino acids seen in the IUGR fetus and may be an adaptation to the deprived milieu associated with uteroplacental insufficiency. Uteroplacental insufficiency is a common and serious complication of pregnancy. It impairs the exchange of metabolites and gases between the mother and fetus, resulting in IUGR. In humans, the metabolic aberrations associated with the IUGR intrauterine milieu include decreased plasma concentrations of the BCAA: leucine, isoleucine, and valine (1-3). Similarly, Ogata et al. (4) found that uteroplacental insufficiency decreased serum BCAA levels in the IUGR fetal rat. Although decreased supply of the BCAA from the placenta contributes to the low plasma levels noted in the IUGR fetus, increased fetal utilization through increased mitochondrial oxidation may also play a role (5). Several investigators have noted that deprivation of the fetal sheep results in decreased serum levels of leucine and increased fetal leucine oxidation (6 -8).Irreversible oxidative decarboxylation of the BCAA is performed by the mitochondrial enzyme BCKAD (9). BCKAD is an enzyme complex composed of four subunits: E1␣, E1␤, E2, and E3. Whereas the first three subunits are specific for BCKAD, the E3 subunit is common among the three keto-acid dehydrogenase complexes (BCKAD, pyruvate dehydrogenase, and ␣-ketoglutarate dehydrogenase). BCKAD activity often correlates with mRNA and protein levels, though covalent modification through phosphorylation and dephosphorylation of the E1␣ subunit determi...

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Uteroplacental insufficiency decreases p53 serine-15 phosphorylation in term IUGR rat lungs

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Uteroplacental insufficiency alters hepatic expression, phosphorylation, and activity of the glucocorticoid receptor in fetal IUGR rats

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