Untitled

Abstract

Desjardins, P. et al., 1999. Effect of portacaval anastomosis on glutamine synthetase protein and gene expression in brain, liver and skeletal muscle. Metabolic Brain Disease, 14(4), p.273-280. ABSTRACTThe effects of chronic liver insufficiency resulting from end-to-side portacaval anastomosis (PCA) on glutamine synthetase (GS) activities, protein and gene expression were studied in brain, liver and skeletal muscle of male adult rats. Four weeks following PCA, activities of GS in cerebral cortex and cerebellum were reduced by 32% and 37% (p<0.05) respectively whereas GS activities in muscle were increased by 52% (p<0.05). GS activities in liver were decreased by up to 90% (p<0.01), a finding which undoubtedly reflects the loss of GS-rich perivenous hepatocytes following portal-systemic shunting. Immunoblotting techniques revealed no change in GS protein content of brain regions or muscle but a significant loss in liver of PCA rats. GS mRNA determined by semi-quantitative RT-PCR was also significantly decreased in the livers of PCA rats compared to sham-operated controls. These findings demonstrate that PCA results in a loss of GS gene expression in the liver and that brain does not show a compensatory induction of enzyme activity, rendering it particularly sensitive to increases in ammonia in chronic liver failure. The finding of a post-translational increase of GS in muscle following portacaval shunting suggests that, in chronic liver failure, muscle becomes the major organ responsible for the removal of excess blood-borne ammonia.

Inhibition of human glutamine synthetase by L-methionine-S,R-sulfoximine—relevance to the treatment of neurological diseases

“…Elevations in cerebral ammonia result in increased levels of glutamine within astrocytes (Brusilow et al 2010, Cooper 2012a, 2012b). Glutamine is a significant osmolyte, and therefore, the increase in its concentrations adds to the brain swelling characteristic of hyperammonemia, particularly in the acute form of this condition (Desjardins et al 1999, Tok et al 2009, Brusilow et al 2010, Mardini et al 2011, Cudalbu et al 2012). Astrocytic glutamine contributes to excitotoxicity by acting as a precursor of the excitatory neurotransmitter glutamate (Ghoddoussi et al 2010, Bame et al 2012).…”

Organ Distribution of 13N Following Intravenous Injection of [13N]Ammonia into Portacaval-Shunted Rats

“…Compared with heart, abdominal muscle accumulated label more slowly and to a lesser extent. Skeletal muscle was not assessed in the previous [18] or present studies, but glutamine synthetase specific activity increases in skeletal muscle of PCS rats [47]. In humans, skeletal muscle is a major sink for removing circulating ammonia [36], presumably via its metabolism to glutamine.…”

“…Since the complete urea cycle is present only in liver, extrahepatic tissues rely on the glutamine synthetase reaction for removal of potentially-toxic ammonia, and the released glutamine is taken up by periportal liver cells wherein glutaminase hydrolyzes the glutamine amide to ammonia for urea synthesis [55]. In PCS rat, total liver glutamine synthetase activity is decreased by up to 90% [47] reflecting a large decrease in its activity in perivenous hepatocytes [58]. Lack of this backup system for removing portal vein ammonia undoubtedly contributes to systemic hyperammonemia in the PCS rats.…”

Hepatic encephalopathy: Ever closer to its big bang

“…It has been suggested that ammonia uptake is increased in CLD and that the subsequent increase in GS capacity is a major alternative pathway for ammonia detoxification[24]. Desjardins et al[25] demonstrated in a porto-cava anastomosis model that GS activity was significantly increased as a result of a post-translational modification of the enzyme.…”