Potential conflict of interest: Nothing to report.
CD73 (ecto-5′-nucleotidase) hepatocyte levels differ across mouse strains and contribute to mallory-denk body formation
Article first published online: 26 AUG 2013
© 2013 by the American Association for the Study of Liver Diseases
Volume 58, Issue 5, pages 1790–1800, November 2013
How to Cite
Snider, N. T., Griggs, N. W., Singla, A., Moons, D. S., Weerasinghe, S. V.W., Lok, A. S., Ruan, C., Burant, C. F., Conjeevaram, H. S. and Omary, M. B. (2013), CD73 (ecto-5′-nucleotidase) hepatocyte levels differ across mouse strains and contribute to mallory-denk body formation. Hepatology, 58: 1790–1800. doi: 10.1002/hep.26525
This work was supported by the National Institutes of Health (grant nos.: R01 DK52951 [to M.B.O.] and K01 DK093776 [to N.T.S.]). and Department of Veterans Affairs Merit Review Award (to M.B.O.). This work utilized Core Services (supported by NIH grant nos.: DK089503 and DK034933; to the University of Michigan).
- Issue published online: 30 OCT 2013
- Article first published online: 26 AUG 2013
- Accepted manuscript online: 31 MAY 2013 08:42AM EST
- Manuscript Accepted: 10 MAY 2013
- Manuscript Received: 14 JAN 2013
- The National Institutes of Health. Grant Numbers: R01 DK52951, K01 DK093776
- Department of Veterans Affairs Merit Review Award (to M.B.O.). This work utilized Core Services (supported by grant nos.: DK089503 and DK034933; to the University of Michigan)
Formation of hepatocyte Mallory-Denk bodies (MDBs), which are aggregates of keratins 8 and 18 (K8/K18), ubiquitin, and the ubiquitin-binding protein, p62, has a genetic predisposition component in humans and mice. We tested the hypothesis that metabolomic profiling of MDB-susceptible C57BL and MDB-resistant C3H mouse strains can illuminate MDB-associated pathways. Using both targeted and unbiased metabolomic analyses, we demonstrated significant differences in intermediates of purine metabolism. Further analysis revealed that C3H and C57BL livers differ significantly in messenger RNA (mRNA) level, protein expression, and enzymatic activity of the adenosine-generating enzyme, ecto-5′-nucleotidase (CD73), which was significantly lower in C57BL livers. CD73 mRNA levels were also dramatically decreased in human liver biopsies from hepatitis C and nonalcoholic fatty liver disease patients. Feeding mice with a diet containing the MDB-inducing agent, 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC), significantly decreased CD73 protein and activity in C57BL livers and resulted in loss of plasma membrane CD73 expression and activity in isolated mouse hepatocytes. To further examine the role of CD73 in MDB formation in vivo, we fed wild-type (WT) and CD73−/− mice a DDC-containing diet. Liver enlargement, p62 induction, and disappearance of the K8/K18 cytoskeleton were attenuated in CD73−/−, compared to WT livers. MDB formation, as assessed by biochemical and immunofluorescence detection of keratin and ubiquitin complexes, was nearly absent in CD73−/− mice. Conclusion: Purine metabolism and CD73 expression are linked to susceptibility to MDB formation in livers of different mouse strains. Expression of the adenosine-generating enzyme, CD73, contributes to experimental MDB induction and is highly regulated in MDB-associated liver injury in mice and in chronic human liver disease. (Hepatology 2013;58:1790–1800)