Mechanism of suppression of urea cycle enzyme gene expression under carnitine deficiency in juvenile visceral steatosis mice.

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Juvenile visceral steatosis (JVS) mice are an animal model of carnitine deficiency, discovered at Kanazawa University, Faculty of Medicine, and suffer from fatty liver, hypoglycemia, hyperammonemia, growth retardation and cardiac hypertrophy. We have shown that hyperammonemia of the mice results from a decrease in the activity and protein amount of all urea cycle enzymes in the liver, caused by suppressed transcription of the enzyme genes. We also showed that all of the symptoms of JVS mice can be completely ameliorated by the administration of carnitine. In this research using primay cultured rat hepatocytes, we report that long-chain fatty acids suppressed the induction of urea cycle enzymes, carbamoylphosphate synthetase I (CPS-I) and argininosuccinate synthetase, by dexamethasone. The addition of long-chain fatty acids also caused activation of AP-1 DNA binding activity in the cultured hepatocytes, as found in the liver JVS mice. These findings, together with the increase of plasma free fatty acids in JVS mice, strongly suggest that the accumulation of long-cahin fatty acids under carnitine deficiency is the major cause of suppression of urea cycle enzyme genes in vivo, resulting in hyperammonemia. Furthermore, we found that nucleotide sequences of promoter and enhancer of mouse CPS-I gene we cloned have a high homology with those of the rat gene and that, notably, there is two AP-1 sites in the enhancer region. We are now investigating the role of the AP-1 sites in the suppression of the gene expression caused by long-chain fatty acids.