Taurine transporter (TauT) deficiency impairs ammonia detoxification in mouse liver

Abstract

Hepatic ammonia handling was analyzed in taurine transporter (TauT) KO mice. Surprisingly, hyperammonemia was present at an age of 3 and 12 months despite normal tissue integrity. This was accompanied by cerebral RNA oxidation. As shown in liver perfusion experiments, glutamine production from ammonia was diminished in TauT KO mice, whereas urea production was not affected. In livers from 3-month-old TauT KO mice protein expression and activity of glutamine synthetase (GS) were unaffected, whereas the ammonia-transporting RhBG protein was down-regulated by about 50%. Double reciprocal plot analysis of glutamine synthesis versus perivenous ammonia concentration revealed that TauT KO had no effect on the capacity of glutamine formation in 3-monthold mice, but doubled the ammonia concentration required for halfmaximal glutamine synthesis. Since hepatic RhBG expression is restricted to GS-expressing hepatocytes, the findings suggest that an impaired ammonia transport into these cells impairs glutamine synthesis. In livers from 12-, but not 3-month-old TauT KO mice, RhBG expression was not affected, surrogate markers for oxidative stress were strongly up-regulated, and GS activity was decreased by 40% due to an inactivating tyrosine nitration. This was also reflected by kinetic analyses in perfused liver, which showed a decreased glutamine synthesizing capacity by 43% and a largely unaffected ammonia concentration dependence. It is concluded that TauT deficiency triggers hyperammonemia through impaired hepatic glutamine synthesis due to an impaired ammonia transport via RhBG at 3 months and a tyrosine nitration-dependent inactivation of GS in 12month-old TauT KO mice. glutamine | hyperammonemia | taurine | scavenger cells | oxidative stress

Significance of taurine transporter (TauT) in homeostasis and its layers of regulation (Review)

“…For many years, researchers were not able to reveal the mechanisms underlying structural liver dysfunction in aged TauT KO mice. Recently, Qvartskhava et al (108) provided the instructive principles of taurine loss by which liver dysfunction of TauT KO mice emerged. Researchers attributed the liver malfunction of TauT KO mice to altered hepatic ammonia handling and hepatic glutamine synthesis in a time-dependent manner.…”

Hepatic cysteine sulphinic acid decarboxylase depletion and defective taurine metabolism in a rat partial nephrectomy model of chronic kidney disease

“…A further taurine abnormality observed here was that in the NxT group there was significantly enhanced hepatic expression of genes encoding taurine transporters TauT and GAT2 (Table 4 ) which perform inwardly directed active transport of taurine in hepatocytes [ 33 , 34 ]. Compensatory up-regulation of the transporters to restore intra-hepatocyte taurine concentration in the face of CSAD insufficiency is a possible explanation.…”

Taurine mitigates cirrhosis-associated heart injury through mitochondrial-dependent and antioxidative mechanisms

“…These data could indicate the profound role of Tau in cardiomyocytes. Taurine deficiency in other organs (e.g., in the liver) or deterioration in its trans-porters (TauT) could also impair fundamental physiological processes such as ammonia detoxification in the liver [ 123 ].…”