Long‐chain fatty acids suppress the induction of urea cycle enzyme genes by glucocorticoid action

Abstract

In order to test the possibility that free fatty acids are the mediator of the abnormal expression of urea cycle enzyme genes in carnitine-deficient juvenile visceral steatosis (JVS) mice, the effects of fatty acids on urea cycle enzyme, carbamoylphosphate synthetase (CPS) and argininosuccinate synthetase (ASS), mRNA levels were examined in rat primary cultured hepatocytes. Addition of a synthetic glucocorticoid hormone, dexamethasone, caused increases in CPS and ASS mRNAs. Further addition of oleic acid suppressed the induction of CPS and ASS mRNAs by dexamethasone. In contrast, the phosphoenolpyruvate carhoxykinase (PEPCK) mRNA level induced by dexamethasone was enhanced in the presence of oleic acid. The effects were reversed on further addition of carnitine. The mRNA levels of these enzymes induced by dibutyryl cAMP were not affected by the addition of oleic acid. A study of the specificity of fatty acids revealed that long-chain fatty acids of more than 16 carbons chain length had a suppressive effect on the CPS mRNA level induced by dexamethasone and that the presence of double bonds enhanced the effect. The changes in gene expression of CPS, ASS and PEPCK caused by the fatty acids in the cultured hepatocytes were very similar to those observed in the liver of JVS mice. The AP-1 DNA binding activity in the presence of dexamethasone was slightly enhanced by the addition of oleic acid. These results suggest that the long-chain fatty acids not metabolized in JVS mice are mediators of the abnormal gene expression in the liver which results in hyperammonemia.

Down-regulation of argininosuccinate synthetase is associated with cisplatin resistance in hepatocellular carcinoma cell lines: implications for PEGylated arginine deiminase combination therapy

“…Other factors have been shown to positively or negatively regulate ASS1 expression. For example, cAMP increases ASS1 expression, while fatty acids cause suppression of this protein [41, 42], and factors such as hormones and pro-inflammatory stimuli are also known to regulate ASS1 expression [39, 43]. …”

Insulin Concentration during Preconditioning Mediates the Regulation of Urea Synthesis during Exposure to Amino Acid-Supplemented Plasma

“…Long-chain fatty acids have been reported to suppress the level of expression of genes encoding urea cycle enzymes. 16 This may contribute to the simultaneous reduction of urea synthesis and enhancement of lipid accumulation observed with the high insulin preconditioned cultures. On the other hand, downregulation of the FAS gene should reduce the level of fatty acid, which is a negative factor in the accumulation of intracellular TG.…”

“…11 In addition, insulin downregulates long-chain acyl-CoA synthetase and its downregulation in turn negatively affects the gene expression level of urea cycle enzymes. 16 Amino acids may regulate gene expression of urea cycle enzymes via long-term control by modulating transcription factors (e.g., C/EBP family). 14 AARE, amino acid response element; UCE, upstream control element.…”

Arginine Deprivation as a Targeted Therapy for Cancer

“…Multiple factors have been shown to positively and negatively influence ASS gene and may be tissue specific. Several investigators have demonstrated that glucocorticoid, glucagon and cyclin AMP increase ASS expression whereas fatty acids repress ASS expression [58][59][60][61][62][63][64][65]. Insulin and growth hormone have negative influence on ASS in liver tissue but no effect in other tissue [66][67][68].…”