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

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE

卷:1812

Article

Renga, Barbara¹  Mencarelli, Andrea¹  Cipriani, Sabrina¹  D'Amore, Claudio¹  Zampella, Angela²  Monti, Maria Chiara³  Distrutti, Eleonora⁴  Fiorucci, Stefano^1,4 

[1] Univ Perugia, Dipartimento Med Clin & Sperimentale, I-06122 Perugia, Italy

[2] Univ Naples Federico II, Dipartimento Chim Sostanze Nat, Naples, Italy

[3] Univ Salerno, Dipartimento Sci Farmaceut & Biomed, Fisciano, Italy

[4] Osped S Maria Misericordia, Perugia, Italy

关键词: Glutamine;    Glutamate;    Urea cycle;    NAGS;    FXR;    Hyperammonemia;   

DOI  :  10.1016/j.bbadis.2011.06.009

来源: Elsevier

【 摘 要 】

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 (CCl4), 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. (C) 2011 Elsevier B.V. All rights reserved.

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