AMPK signaling regulates expression of urea cycle enzymes in response to changes in dietary protein intake

Abstract

Abundance of urea cycle enzymes in the liver is regulated by the dietary protein intake. Although urea cycle enzyme levels rise in response to a high protein diet, signaling networks that sense dietary protein intake and trigger changes in expression of urea cycle genes have not been identified. The aim of this study was to identify signaling pathway(s) that respond to changes in protein intake and regulate expression of urea cycle genes in mice and human hepatocytes. Mice were adapted to either control or high (HP) protein diets followed by isolation of liver protein and mRNA and integrated analysis of the proteomic and transcriptome profiles. HP diet led to increased expression of mRNA and enzymes in amino acid degradation pathways, and decreased expression of mRNA and enzymes in carbohydrate and fat metabolism, which implicated AMPK as a possible regulator. Primary human hepatocytes, treated with AICAR an activator of AMPK, were used to test whether AMPK regulates expression of urea cycle genes. The abundance of CPS1 and OTC mRNA increased in hepatocytes treated with AICAR, which supports a role for AMPK signaling in regulation of the urea cycle. Because AMPK is either a target of drugs used to treat type-2 diabetes, these drugs might increase the expression of urea cycle enzymes in patients with urea cycle disorders, which could be the basis of a new therapeutic approach.

Editorial

“…Today, such models are critical not only for the understanding of disease mechanisms, but are also essential for testing and development of novel therapies. Pathophysiological aspects are presented by reports from Ljubica Caldovic et al dealing with regulation of urea cycle enzymes by specific kinase signaling, from Nicola Brunetti‐Pierri et al on the relationship between ammonia and autophagy, from Rossella Parini et al on energy expenditure aspects in argininosuccinate lyase deficiency, from Carlo Dionisi‐Vici et al on chronic liver involvement in urea cycle defects, and from Leandro Soria et al on the effect of glutamine synthetase augmentation on ammonia detoxification . Four additional articles focus on patient aspects: diagnosis, (dietary) treatment, management of adult patients, including neuropsychological aspects, and therapeutic prospects for urea cycle defects .…”