wild-type mice. Interestingly, also 50% of heterozygous taut+/- mice develop liver disease at an age beyond 1 year. Thus, it appears that both homo- and heterozygous taut knockout mice are prone to unspecific hepatitis and liver fibrosis, but the process may evolve slower in taut+/- mice than in taut—/— mice.
Hepatocyte destruction and apoptosis are hallmarks of liver pathology in taut—/— mice (Warskulat et al., 2006b). The progressive loss of hepatocytes is expected to stimulate hepatocyte proliferation. In taut—/— mice, this regenerative process apparently involves oval cell proliferation, which is found abundantly in livers from taut—/— mice with chronic hepatitis beyond 1 year of age.
Activation of the CD95 system was found in liver tissue of taut—/— mice: increased epidermal growth factor (EGFR) activation, EGFR/CD95 complex formation, and high levels of tyrosine-phosphorylated CD95 with death-inducing complex recruitment (Warskulat et al., 2006b). These events were shown to be required for CD95 membrane trafficking, CD95 activation, and apoptosis induction in hepatocytes (Reinehr et al., 2003a,b, 2004a,b). Activation of the CD95 system is also found in livers from taut+/- mice, however, to a lesser degree than in taut—/— mice (Warskulat et al., 2006b). No increase in tyrosine-nitrated CD95 is found in livers from taut-deficient animals, suggesting that no antiapoptotic nitration of CD95 occurred (Reinehr et al., 2004b). Hydrophobic bile acids are known to trigger hepatocyte apoptosis through activation of the CD95 system (Graf et al., 2002). However, the bile acid conjugation pattern is normal in taut—/— mice (Warskulat et al., 2006b). Thus, an increased bile acid-induced activation of the CD95 system in livers from taut—/— mice seems unlikely. Activation of the hepatic CD95 system in taut+ /— and taut—/— mice is accompanied by an increased number of apoptotic cells, as shown by staining for activated caspase 3 (Warskulat et al., 2006b). Exposure of young (10 weeks old) wildtype and taut—/— mice in vivo to an acute oral dose of ethanol (6 g/kg body weight) leads to a stronger activation of the CD95 system in taut—/— liver, suggesting that livers from taut-deficient mice are more susceptible to liver damage by ethanol (Warskulat et al., 2006b).
In summary, several mechanisms may contribute to activation of the CD95 system in taut—/— and taut+/— mice: (i) Taurine depletion may lead to hepatocyte shrinkage, which was shown to activate the CD95 system (Reinehr and Haussinger, 2006; Reinehr et al., 2003a,b, 2004a,b); (ii) taurine acts as an antioxidant and taurine deficiency may augment the formation of reactive oxygen species (ROS), which are known upstream triggers of CD95 activation (Medan et al., 2005); (iii) TAUT deficiency results in mitochondrial abnormalities (Warskulat et al., 2006b), which may further augment ROS formation; and (iv) increased tumor necrosis factor-a levels in the plasma of taut-deficient mice (Warskulat et al., 2006b) point to an upregulation of proapoptotic cytokines following osmotic stress.
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