Roles of changes in active glutamine transport in brain edema development during hepatic encephalopathy: an emerging concept.
Excessive glutamine (Gln) synthesis in ammonia-overloaded astrocytes contributes to astrocytic swelling and brain edema, the major complication of hepatic encephalopathy (HE). Much of the newly formed Gln is believed to enter mitochondria, where it is recycled to ammonia, which causes mitochondrial dysfunction (a "Trojan horse" mode of action). A portion of Gln may increase osmotic pressure in astrocytes and the interstitial space, directly and independently contributing to brain tissue swelling. Here we discuss the possibility that altered functioning of Gln transport proteins located in the cellular or mitochondrial membranes, modulates the effects of increased Gln synthesis. Accumulation of excess Gln in mitochondria involves a carrier-mediated transport which is activated by ammonia. Studies on the expression of the cell membrane N-system transporters SN1 (SNAT3) and SN2 (SNAT5), which mediate Gln efflux from astrocytes rendered HE model-dependent effects. HE lowered the expression of SN1 at the RNA and protein level in the cerebral cortex (cc) in the thioacetamide (TAA) model of HE and the effect paralleled induction of cerebral cortical edema. Neither SN1 nor SN2 expression was affected by simple hyperammonemia, which produces no cc edema. TAA-induced HE is also associated with decreased expression of mRNA coding for the system A carriers SAT1 and SAT2, which stimulate Gln influx to neurons. Taken together, changes in the expression of Gln transporters during HE appear to favor retention of Gln in astrocytes and/or the interstitial space of the brain. HE may also affect arginine (Arg)/Gln exchange across the astrocytic cell membrane due to changes in the expression of the hybrid Arg/Gln transporter y(+)LAT2. Gln export from brain across the blood-brain barrier may be stimulated by HE via its increased exchange with peripheral tryptophan.
Department of Neurotoxicology, Mossakowski Medical Research Centre, Polish Academy of Sciences, Pawinskiego St. 5, 02-106, Warsaw, Poland, mzielinska@imdik.pan.pl.
Magdalena
M
Zielińska
Mariusz
M
Popek
Jan
J
Albrecht
D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D001929:Brain Edema / Q000209:etiology / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism*; D006501:Hepatic Encephalopathy / Q000378:metabolism*; D006801:Humans; D008954:Models, Biological
D002352:Carrier Proteins; C037853:glutamine transport proteins