Suppressed expression of the urea cycle enzyme genes in the liver of carnitine-deficient juvenile visceral steatosis (JVS) mice in infancy and during starvation in adulthood.

Systemic carnitine-deficient juvenile visceral steatosis (JVS) mice exhibit decreased expression of some liver-selective genes including those for the urea cycle enzymes during the infantile period. At 25 days, carbamoylphosphate synthetase (CPS) mRNA level was remarkably low in the liver of JVS mice, and the HNF-4 and C/EBP-alpha mRNA contents were also reduced. HNF-3 alpha and C/EBP-beta mRNAs were slightly higher in the liver of JVS mice, and HNF-1 mRNA remained normal. These results, together with the developmental changes of these transcription factor mRNA levels, suggest that HNF-4 and C/EBP-alpha are involved in the suppression of CPS expression. If JVS mice survived the crisis at 4-5 weeks, their body weight caught up with that of control mice around 7 weeks. The steady-state levels of CPS and argininosuccinate synthetase (ASS) mRNAs in the liver of JVS mice were normalized by no later than 8 weeks. Starvation for 48 h caused an increase of about twofold in CPS and ASS mRNA levels in the liver of control mice, while the same treatment failed to increase their levels in the liver of JVS mice. The starvation similarly caused increases in HNF-4 and C/EBP-beta mRNA levels in the liver of both control and JVS mice, but the increases were significantly less in JVS mice than in control mice. Thus, the lack of induction of CPS and ASS mRNAs during development and under starvation in JVS mice correlated with the lower induction of HNF-4 and C/EBP-alpha mRNAs, and of HNF-4 and C/ EBP-beta mRNAs, respectively. Furthermore, all these changes seemed to correlate with the presence of fatty liver and the high serum free fatty acid levels, suggesting that disturbance of fatty acid metabolism affects nitrogen metabolism at least in part via altered gene expression of transcription factors such as HNF-4, C/EBP-alpha, and C/EBP-beta.