The nuclear receptor FXR regulates hepatic transport and metabolism of glutamine and glutamate.

Abstract

Hepatic transport and metabolism of glutamate and glutamine are regulated by intervention of several proteins. Glutamine is taken up by periportal hepatocytes and is the major source of ammonia for urea synthesis and glutamate for N-acetylglutamate (NAG) synthesis, which is catalyzed by the N-acetylglutamate synthase (NAGS). Glutamate is taken up by perivenous hepatocytes and is the main source for the synthesis of glutamine, catalyzed by glutamine synthase (GS). Accumulation of glutamate and ammonia is a common feature of chronic liver failure, but mechanism that leads to failure of the urea cycle in this setting is unknown. The Farnesoid X Receptor (FXR) is a bile acid sensor in hepatocytes. Here, we have investigated its role in the regulation of the metabolism of both glutamine and glutamate. In vitro studies in primary cultures of hepatocytes from wild type and FXR(-/-) mice and HepG2 cells, and in vivo studies, in FXR(-/-) mice as well as in a rodent model of hepatic liver failure induced by carbon tetrachloride (CCl(4)), demonstrate a role for FXR in regulating this metabolism. Further on, promoter analysis studies demonstrate that both human and mouse NAGS promoters contain a putative FXRE, an ER8 sequence. EMSA, ChIP and luciferase experiments carried out to investigate the functionality of this sequence demonstrate that FXR is essential to induce the expression of NAGS. In conclusion, FXR activation regulates glutamine and glutamate metabolism and FXR ligands might have utility in the treatment of hyperammonemia states.

• Authors: Barbara Renga, Andrea Mencarelli, Sabrina Cipriani, Claudio D'Amore, Angela Zampella, Maria Chiara Monti, Eleonora Distrutti, Stefano Fiorucci
• Journal: Biochimica et biophysica acta (Biochim Biophys Acta) Vol. 1812 Issue 11 Pg. 1522-31 (Nov 2011) ISSN: 0006-3002 [Print] Netherlands
• PMID: 21757002 (Publication Type: Journal Article)
• Copyright: 2011 Elsevier B.V. All rights reserved.

Chemical References

• Glutamates
• RNA, Messenger
• Receptors, Cytoplasmic and Nuclear
• farnesoid X-activated receptor
• Glutamine
• Carbon Tetrachloride
• Luciferases
• Amino-Acid N-Acetyltransferase
• NAGS protein, human
• Nags protein, mouse
• N-acetylglutamic acid

Topics

• Amino-Acid N-Acetyltransferase (genetics, metabolism)
• Animals
• Blotting, Western
• Carbon Tetrachloride (toxicity)
• Cell Nucleus
• Chromatin Immunoprecipitation
• Electrophoretic Mobility Shift Assay
• Glutamates (metabolism)
• Glutamine (metabolism)
• Hep G2 Cells
• Hepatocytes (cytology, metabolism)
• Humans
• Hyperammonemia (chemically induced, metabolism)
• Liver Cirrhosis, Experimental (chemically induced, metabolism)
• Luciferases (metabolism)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Promoter Regions, Genetic (genetics)
• RNA, Messenger (genetics)
• Receptors, Cytoplasmic and Nuclear (physiology)
• Reverse Transcriptase Polymerase Chain Reaction