Hyperammonemia in carnitine-deficient adult JVS mice used by starvation.

Juvenile visceral steatosis (JVS) mouse is an animal model of human primary carnitine deficiency caused by a mutation of the gene encoding carnitine transporter, and suffers from various symptoms, such as fatty liver, growth retardation, hyperammonemia, hypoglycemia, and cardiac hypertrophy. We have shown that hyperammonemia during the weaning period (15-26 days of age) is caused by suppression of urea cycle enzyme gene expression. The suppression resulted from activation of a transcription factor, AP-1. We have found that a cis-element for AP-1 binding is present in the enhancer region of the carbamoylphosphate synthetase (CPS) gene, and that the AP-1 binding site is involved in the suppression of CPS induction by dexamethasone in cultured hepatocytes and in the suppression of CPS expression in the liver of JVS mice. The blood ammonia levels in JVS mice increased during the weaning period, and then decreased to almost control levels after 30 days of age. In this paper, we report that in adult JVS mice, ammonia levels again increased after starvation for at least 24 hr and this effect was suppressed by carnitine treatment. Starvation for 48 hr did not significantly suppress CPS activity in the liver and did not cause any change in hepatic ornithine concentration. The concentration of N-acetylglutamate in the liver of starved JVS mice was not significantly different from that of JVS mice treated with carnitine. These results indicate that the hyperammonemia in carnitine-deficient adult JVS mice during starvation and the suppression by carnitine treatment differ from those found during the weaning period, and thus the cause of hyperammonemia and the mechanism of suppression remain to be solved.