680
liver sections from APAP-injected PTP1B
-/-
mice as compared to the wild-type
controls that presented histological signs of severe hepatotoxicity (Figure 8B).
PTP1B-deficient mice are protected against liver damage induced at a high
dose of APAP.
We next determined if reduced sensitivity of PTP1B
-/-
mice to APAP-
induced liver injury was associated with alterations in basal GSH levels in the two
mose strains. Interestingly, the basal expression of Cyp2e1, GCL-C and GCL-M and
basal GSH levels were comparable among both genotypes of mice (Figure 8C, 8D).
Figure 8.- PTP1B-deficient mice are protected against liver damage induced by a high dose of
APAP under similar GSH levels and expression of Cyp2e1, GCL-C, GCL-M and BclxL in the
liver.
PTP1B
+/+
and PTP1B
-/-
mice were injected with 500 mg/kg APAP or saline for 6 h.
A
. ALT
activity.
**
P<0.01 PTP1B
-/-
vs. PTP1B
+/+
mice (n= 6-8 mice of each condition).
B
. Representative
Hematoxylin & Eosin staining in liver sections. Bar scale 100 µm.
C.
Basal GSH levels in livers from
PTP1B
+/+
and PTP1B
-/-
mice.
D.
Whole cell lysates from both mice +were analyzed by Western blot
with the indicated antibodies. Representative autoradiograms are shown.
4. CONCLUSION
In summary, the present study provides the first molecular evidence that
levels of PTB1B modulate susceptibility to apoptosis that occurred at early time-
periods in hepatocytes treated with toxic doses of APAP. Thus, our results have
revealed that PTP1B inhibition might be therapeutically of interest against the
hepatotoxicity induced by overdoses of APAP.
5. ACKNOWLEDGEMENTS
We acknowledge the following grant support: SAF2012-33283 (MINECO,
Spain), Comunidad de Madrid S2010/BMD-2423, EFSD and Amylin Paul
Langerhans Grant and Centro de Investigación Biomédica en Red de Diabetes y
Enfermedades Metabólicas Asociadas (CIBERDEM, ISCIII, Spain).
