Taurine deficiency induces hyperammonemia and oxidative stress and senescence in mouse liver

Introduction:

Taurine is the most abundant amino acid in the body and an important osmolyte, antioxidant, chaperone and immunomodulator. Resent study showed that taurine transporter (TauT) knockout induces fibrosis and unspecific inflammation in the liver at an age of 15 – 17 months. In the present study, we analyzed effects of taurine depletion in TauT-KO mice on ammonia metabolism, oxidative stress and senescence in livers from 3 or 12 months old mice.

Material and methods:

Blood ammonia levels were measured using Ammonia Checker II. Protein and RNA were isolated from livers of 3 and 12 months old TauT-KO and WT mice. Expression levels of mRNA or proteins were quantified by realtime PCR or Western blot and immunofluorescence analysis, respectively.

Results:

Liver architecture was preserved and expression levels of collagens I, III and IV were unchanged in livers of 3 and 12 months old TauT-KO mice indicating absence of fibrosis. Likewise, expression levels of surrogate marker for inflammation such as macrophage activation markers F4/80 and CD14 and mRNA levels of pro-inflammatory cytokines were similar in livers of 3 and 12 months old TauT-KO mice. Blood ammonia levels were elevated in TauT-KO mice at both ages but expression levels of urea cycle enzymes, glutamine synthetase (GS) or glutaminase were similar at the mRNA and protein level in TauT-KO compared to the WT mice. However, expression of the ammonia transporter RhBG was strongly decreased in TauT-KO mice at 3 months but unchanged in 12 months old mice compared to WT. GS activity in liver was normal at 3 months but at 12 months old TauT-KO mice GS activity was decreased to 60% of WT. Loss of GS activity in livers of 12 months old TauT-KO mice was accompanied by tyrosine nitration of about 40% of GS protein. Expression levels of surrogate markers for oxidative stress (NO2Tyr, 8OH(d)G) and senescence (p-p53, p-21, GADD45α) were upregulated in livers of 12 months old TauT-KO.

Conclusion:

The results of our study demonstrate that taurine depletion impairs ammonia detoxification in mouse liver and this is associated with oxidative stress and senescence. Hyperammonemia in 3 months old TauT-KO mice may result from impaired ammonia uptake by the scavenger cells via RhBG. At the age of 12 months however, tyrosine nitration mediated inactivation of GS may account for impaired ammonia detoxification and hyperammonemia.